Method and system for consistent, repeatable, and safe cryospray treatment of airway tissue

ABSTRACT

A method and system for automated and semi-automated predictable, consistent, safe, effective, and lumen-specific and patient-specific cryospray treatment of airway tissue in which treatment duration is automatically set by the system following entry of patient information and treatment location information into the system by the user, and treatment spray is automatically stopped by the system when the automatically selected treatment duration has been achieved as determined by the system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.16/663,773, filed Oct. 25, 2019, which is a continuation of U.S. patentapplication Ser. No. 14/731,359, filed on Jun. 4, 2015, now granted asU.S. Pat. No. 10,492,843, which claims priority under 35 U.S.C. § 119 toU.S. Provisional Patent Application No. 62/047,936 by Hanley et al.titled “Bronchoscopic Sheath For Measuring or Spacing” and filed Sep. 9,2014 and to U.S. Provisional Patent Application No. 62/007,518 byManers, et al. titled “Method and System For Consistent, Repeatable, andSafe Cryospray Treatment of Airway Tissue” and filed Jun. 4, 2014. Eachof the foregoing applications is incorporated by reference in itsentirety and for all purposes.

FIELD OF THE INVENTION

The present invention relates to medical devices for treating pulmonarydiseases, more specifically to cryospray devices.

BACKGROUND OF THE INVENTION

The conducting airways of humans are lined by a superficial layer ofepithelial cells which comprise an important primary line of defense tothe entire respiratory tract. This superficial cellular layer consistsprimarily of mucus-producing (goblet) cells and ciliated cells. Thesecells function in a coordinated fashion to entrap inhaled biological andinert particulates and remove them from the airways. While this“mucociliary escalator” functions with great efficiency in the face ofpotentially injurious stimuli, it is a delicately balanced systemrelying on maintenance of appropriate complements of ciliated andmucus-producing cells and the normal functioning of those cells toaccomplish effective clearance. Perturbations in epithelial cell typedistribution and function can lead to adverse health effects.

Ciliated cells represent approximately 80% of the epithelial cellsresiding on luminal borders of the large airways. While they are themost prevalent epithelial cell type lining the airways, many studiessuggest that they also are among the most vulnerable to injury byinfection, irritant, and pollutant exposure. The identifyingcharacteristic of ciliated cells, are the highly organized appendages ofthe cell, i.e., the cilia which cover the luminal border.

Mucus and other non-ciliated cells represent approximately 20% of theepithelial cells lining the luminal borders of the large airways. Mucuscells often are distended with secretory product and exhibit acharacteristic “goblet” shape. Together with the submucosal glands,goblet cells secrete high molecular weight mucus glycoproteins (mucins).Goblet cells are thought to have the potential to produce markedly moremucus than do the glands, especially in response to injury such asenvironmental pollutants and other noxious elements such astobacco/cigarette smoke.

Other non-ciliated cells with fewer or no granules also may be presentalong the luminal border. These may represent mucus cells which haveemptied their contents onto the luminal surface or cells which have notyet differentiated. The entire epithelial layer sits on a basementlamina comprised of collagen and connective tissue. All the cells of theepithelial layer are anchored to this “basement membrane.”

Chronic bronchitis is a non-infectious inflammatory disease typicallyresulting from airway injury due to a noxious element (usually smoking).It is defined by cough with productive sputum of three months durationfor two consecutive years. It is further characterized by excess mucus(mucus hyperactivity/hypersecretion/hyperplasia of goblet cells) in thebronchi, damage to cilia and loss of ciliated cells. Noxious stimulilead to airway inflammation with swelling of the lamina propria leadingto thickening of the airway wall, and this functional narrowing causesshortness of breath. More specifically, this injury causesover-proliferating goblet cells to over-produce a thick viscous, acidicmucus which is difficult to clear due to cilia dysfunction. The acidicmucous in chronic bronchitis leads to inflammation of the airway walland varies in viscosity.

Asthma is a chronic respiratory disease characterized by bronchialinflammation, increased airway smooth muscle and airwayhyper-responsiveness, in which airways narrow (constrict) excessively ortoo easily in response to a stimulus. Asthma episodes or attacks causenarrowing/constriction of the airways, which makes breathing difficult.Asthma attacks may occur at irregular intervals and be triggered byallergens or irritants that are inhaled into the lungs or by stress,cold air, viral infections or other stimuli. Asthma is sometimes, butnot always, associated with mucus hyperactivity.

Airway hypersecretion is a feature of other airway diseases as well,including chronic obstructive pulmonary disease (COPD), cystic fibrosis,viral bronchitis, and bronchiolitis.

In an individual suffering from hypersecretion, mucus accumulates in theairways and may cause airway obstruction. Airway submucosal glands andgoblet cells lining the airway epithelium secrete mucus, an adhesive,viscoelastic gel composed of water, carbohydrates, proteins, and lipids.In a healthy individual, mucus is a primary defense against inhaledforeign particles and infectious agents and is cleared by activecolumnated cilial cells/movement which assists in clearing the mucus inan upward direction where it is either swallowed or eliminated via aproductive cough. Mucus traps these particles and agents and facilitatestheir clearance while also preventing tissues from drying out. Smallairways that contain goblet cells as well as peripheral airways andwhich cannot be cleared by cough are particularly vulnerable to mucusaccumulation and gradual obstruction by mucus.

Conventional treatments for individuals suffering from airwayhypersecretion or chronic bronchitis include use of systemic or inhaledcorticosteroids, anticholinergics, antibiotic therapy, bronchodilators(e.g., methylxanthines), short or long-acting beta2-agonists which relaxthe muscles in the airways to relieve symptoms, aerosol delivery of“mucolytic” agents (e.g., water, hypertonic saline solution), and oraladministration of expectorants (e.g., guaifenesin). It should be notedthat while these medications are variably approved by the FDA for use inCOPD they are not specific for chronic bronchitis with the exception ofroflumilast, an inhibitor of an enzyme called phosphodiesterase type 4(PDE-4).

Many of the above described medications have serious side effects. Forexample, inhaled corticosteroids can cause thrush (a yeast infection ofthe mouth), cough, or hoarseness, and systemic corticosteroids have evenmore severe side effects, such as delayed sexual development, changes inmenstrual cycle, weight gain, and increased blood sugar (diabetes). Theside effects of methylxanthines include severe nausea, tremors, muscletwitching, seizures, and irregular heartbeat. Roflumilast commonlyinduces significant diarrhea. Patient compliance is often low due tothese side-effects.

Interventional approaches to managing occluded airways include surgery,mechanical debulking, brachytherapy, stents, photodynamic therapy, andthermal modalities, such as electrocautery, laser, argon plasmacoagulation, and bronchial thermoplasty. Bronchial thermoplasty is aprocedure designed to help control severe asthma by reducing the mass ofairway smooth muscle by delivering thermal energy to the airway wall,heating the tissue in a controlled manner. Bronchial thermoplasty withRF energy creates a deep ablation effect down to the level of the airwaysmooth muscle creating a reparative healing that results in scar tissuewhich is fibrotic in nature. Hyper-thermal treatment denatures proteins,and causes enyzme inactivation and prevents collagen remodeling.Accordingly, bronchial thermoplasty patients cannot be re-treated in thesame areas. Cryoprobes have also been used in airway management, buttheir use can be tedious and time-consuming because of surface arealimitations of the probes, which requires contact between the probe andthe surface of the targeted lesion or tissue.

Reports of promising results from use of low-pressure spray cryotherapyfor ablation of esophageal lesions (Barrett esophagus, dysplasia andesophageal cancers) led Krimsky, et al. to gauge the safety of usingcryospray in airway tissues. Krimsky, et al., 2009. Krimsky, et al.,reported performing spray cryotherapy on 21 subjects who were scheduledfor lung resection for treatment of lung cancer, carcinoid tumor andmycobacterial infection. Treatment areas were directed to normal andunrestricted portions of the airway distal to planned anastomotic sites.All sites received a targeted delivery of low-pressure (2-3 psi) liquidnitrogen of identical dosimetry, 2 cycles of 5-second spray with a60-second interval thaw. All patients had treatment times shorter than 5minutes. Post-treatment bronchoscopic and histologic examinations ofairways were conducted from less than 1 day to 106 days after treatment.

Findings from the treated areas revealed varying levels of cryonecrosis,limited to the mucosal and submucosal layers (approximately 1.5 mm), andchanges consistent with recent tissue injury with no damage toconnective tissue. Krimsky, et al. reported loss of epithelium andairway smooth muscle, edema, and damaged submucosal glands at early timepoints post-treatment, followed by adjacent re-epithelialization andhealing centrally from the margin of the injury. Completere-epithelialization of the airway mucosa and a thinned or absent smoothmuscle layer, as well as some continued thinning of the submucosalglands was reported to persist to 106 days after treatment.

Krimsky, et al. reported that these initial safety and histologicassessments suggested that spray cryotherapy may be safe and conduciveto treatment of the airways by causing focal injury to the cellularelements of treated tissue without damage to underlying connectivetissue, i.e., the extracellular matrix. Acknowledging the small numberof the subjects in the study, and particularly noting that only normal,unobstructed airways were treated, Krimsky et al. nevertheless positedthat the results of that study suggest treatment possibilities in humanthoracic diseases.

Notably, in addition to only treating healthy unobstructed tissue (notreatment of regions characterized by excess goblet cells,hypersecretion, or damaged or lost cilia), Krimsky, et al. reported noobservations concerning mucous production, goblet cell population orproliferation, and or cilia/ciliated cell population, either pre- orpost-treatment. Additionally, Krimsky et al. made no observations orsuggestions that cryospray treatment can actually cause change inarchitecture of diseased/damaged tissue, and no suggestion that diseasedsections could be regenerated as healthy tissue. Moreover, there havebeen no published studies since Krimsky, et al. that have addressedthese questions. Indeed, as of this writing, there are no medications ordevices today that propose reduction in mucous secreting cells, and/orremodeling of cilia.

SUMMARY OF THE INVENTION

Cryospray methods and devices of the prior art, while effective toprovide approximate cryospray amounts for approximate cryospraydurations, are not configured to deliver precise and consistentcryospray doses from device to device, and even from use to use by thesame user using the same device. Yet the prior art cryospray devices andmethods have met a long-felt need in the industry, and excellenttreatment results have been reported from the use of prior art cryospraydevices. According to current cryospray devices and methods, the spraypedal is pressed, the surgeon waits for the cryospray to travel throughthe system and delivery catheter to exit the catheter tip, observes thecryospray application to the desired tissue through the endoscope orbronchoscope, continues the spray until the treated tissue turns white,generally recognized as indicating that the tissue has achieved a frozenstate, then manually continues on with the spray for a measured amountof time such as five or up to ten seconds. The flow of cryogen isimmediately stopped by the treating physician releasing the pedal. Thetreated tissue is allowed to thaw, then the treatment is repeated in thesame fashion, if desired. In short, current cryospray devices andmethods are designed to ablate tissue, and the amount of cryosprayapplied varies from patient to patient, and surgeon to surgeon, based onthe surgeon's observation of the change in tissue during treatment,making a subjective assessment concerning progress of the treatment andmaking a subjective determination concerning whether additionaltreatment of the treated area is indicated. Surgeons and other users ofthe prior art cryospray devices and methods are trained and comfortablewith the current method of cryospray, and are reporting excellentresults. Accordingly, there has been no need perceived in the art for acryospray method or device that performs differently than the prior artcryospray methods and devices.

Notwithstanding the foregoing, and even taking into account theexpertise and experience of surgeon users, the inventors have discoveredthat treatment of a superficial depth of tissue in airways that do nothave obstructions from excess tissue, tumors or fibrotic tissue, for thepurpose of triggering tissue regeneration requires cryospray devices andmethods that provide automated or semi-automated cryospray applicationto airway tissue that is predictable, consistent and repeatable, fromapplication to application and from device to device, and that isspecifically and individually tailored to each patient and to eachsegment of airway tissue. In order to provide such predictable,consistent, and repeatable cryospray application (the need for which wasnot previously appreciated in the art), the inventors developed thedevices and methods described herein.

According to the invention, therefore, the present invention is a methodand system for automated and semi-automated predictable, consistent,effective, lumen-specific dose(s) and patient-specific cryosprayextended treatment of airway tissue, across one or more treatmentsessions. According to one embodiment of the invention, treatmentduration is automatically set by the system following entry of patientinformation and treatment location information into the system by theuser, and treatment spray is automatically stopped by the system whenthe automatically selected treatment duration has been achieved asdetermined by the system. According to another embodiment of theinvention, different treatment durations are automatically set fordifferent treatment locations in the airway based on treatment siteluminal diameter. According to another embodiment of the invention,treatment spray cannot occur until a user enters patient information andtreatment location into the system console.

According to another embodiment of the system, the device is configuredto maintain the cryospray supply line between the onboard cryogen tankand the delivery catheter port at a constant temperature duringcryospray operation. According to a preferred embodiment, the cryospraysupply line between the cryogen tank and the delivery catheter port ismaintained at a constant temperature above (warmer than) −120 C, andpreferably at or around 20 C using combinations of sensors and heatersat the control valves and at the end piece.

According to yet another embodiment of the invention, each individualdelivery console is calibrated and tuned so that each delivery consoleprovides a nearly identical automated dosage for each set of deliveryparameters, i.e., patient information and treatment location/luminaldiameter. According to this embodiment, a fully assembled and operatingcryospray delivery console, already charged with cryogen, is connectedto an external source of cryogen (in gaseous form) via an adjustablepressure valve. The adjustable pressure valve is used to dial in aspecific and precise tank pressure. The cryospray delivery system isthen operated in test mode, and that cooling power is measured at thecryospray outlet, i.e., the tip of the cryospray delivery catheter. Theadjustable pressure valve is then adjusted, and the system re-testeduntil the desired cooling power is achieved at the outlet. Once thepressure necessary to achieve the desired cooling power has beendetermined, the console is tuned to set the nominal cryogen tankpressure to the determined pressure. According to this embodiment,notwithstanding variations from machine to machine due to manufacturingtolerances for tubing, valves, and other cryogen supply elements, eachcryospray device according to the invention delivers the exact cryospraydose for each set of delivery parameters, i.e., patient information andluminal diameter.

According to a further embodiment of the invention, there is provided animproved cryogen delivery catheter having a proximal segment that iswider than the working channel of a corresponding bronchoscope, and adistal segment that is configured to fit within the working channel of acorresponding bronchoscope. According to yet another embodiment,treatment of airway tissue is administered circumferentially using aradial spray pattern delivery catheter configured to deliver a cryosprayto the entire circumferential interior of a selected endoluminalcross-section simultaneously without having to rotate the deliverycatheter. According to this embodiment, the distal end of the catheteris configured to direct cryospray radially relative to the axis of thedelivery catheter, and not forward (i.e., not longitudinally, relativeto the axis of the delivery catheter). According to this embodiment, thedistal end of the delivery catheter is configured with exactly two rowsof eight cryogen delivery ports, equally spaced around the perimeter ofthe catheter, the center line of the rows preferably displaced 0.025″from one-another, and each port offset from an adjacent port of theother row by 22.5°. The inventors have discovered that prior radialcryospray delivery port arrangements having more than two rows ofdelivery ports tend to produce a cryogen delivery pattern that extendsforward, often beyond the visualization limits of the bronchoscope.Moreover, the inventors discovered that the two, offset rows of deliveryports described herein avoid the forward traveling cryospraycharacterized by delivery catheters that have more than two rows ofdelivery ports.

These embodiments, together with others as explained in more detailherein, provide an automated and semi-automated predictable, consistent,safe, effective, and lumen-specific and patient-specific cryospraytreatment of diseased airway tissue.

Another aspect of the present invention, therefore, is the therapeutictreatment of epithelial hyperplasia and metaplasia using the methods anddevices of the present invention. The treatments can also be used, forexample, therapeutically to ameliorate altered epithelial architecturein the setting of asthma, bronchitis, bronchiolitis, and/or relatedinflammatory and infectious disorders characterized by a similar patternof goblet cell metaplasia and/or increased airway smooth muscle. Thetreatments can similarly be used to treat an airway disease or conditioncharacterized by hypersecretion of mucus.

Disease states indicative of a need for cryospray therapy include, forexample, chronic obstructive pulmonary disease, inflammatory diseases(e.g., asthma, bronchiectasis, and pulmonary fibrosis), and chronicobstructive lung diseases (e.g., chronic bronchitis).

A determination of the need for treatment may be assessed according toany number of ways, including but not limited to one or more of thefollowing—a history and physical exam, histopathology (biopsyconfirmation) consistent with over production of mucus or goblet cellproliferation (e.g., cough productive of mucous), radiographic or otherimaging studies of the airways that indicate diseases or conditions withoverproduction of mucous, or pulmonary function tests that indicateevidence of airway obstruction and/or hyperreactivity.

According to the present invention, a method is presented for spraycryotherapy directed to at the airway surface epithelium to destroydamaged cilia and hypersecretory goblet cells and to stimulate/or induceremodeling resulting in regenerative healing response or remodelingresulting in new tissue/cell growth, new cilia, new epithelium resultingin reduced mucous production. According to the invention, the airwaytissue response to cryospray treatment is a regenerative healingresponse, i.e., resulting in tissue remodeling, as compared to areparative healing response leading to scar/fibrosis. As cryosprayresults in a preservation of the extracellular matrix with littlescarring or fibrotic tissue healing, cryospray treated regions can bere-treated in the same areas in the event that treated and remodeledtissue suffers a relapse after remodeling/regeneration.

According to an aspect of the invention, there is presented a method forcryospray treatment of damaged, inflammatory, or hypersecretory airwaytissue which causes airway remodeling resulting in return of airwayepithelium to healthy architecture.

According to an aspect of the invention, there is presented a method forcryospray treatment of treating airway hypersecretion which causesairway remodeling and therapeutic reduction of mucous hypersecretion.

According to an aspect of the invention, there is presented a method forcryospray treatment of damaged, inflammatory, or hypersecretory airwaytissue wherein the application/delivery of cryogen is touch free.

According to an aspect of the invention, there is presented a method forcryospray treatment of damaged, inflammatory, or hypersecretory airwaytissue which does not require apposition of the cryospray instrument tothe target tissue.

According to an aspect of the invention, there is presented a method forcryospray treatment of damaged airway cilia.

According to an aspect of the invention, there is presented a method forcryospray treatment of chronic bronchitis.

According to an aspect of the invention, there is presented a method forcryospray treatment of asthma-associated bronchial obstruction due tomucous hyperactivity.

According to an aspect of the invention, there is presented a method forcryospray treatment of asthma-associated bronchial obstruction due toincreased airway smooth muscle.

According to an aspect of the invention, there is presented a method forcryospray treatment of COPD.

According to an aspect of the invention, there is presented a method forcryospray treatment of overproduction of or hyperplasia of goblet cellsin the airway.

According to an aspect of the invention, there is presented a method forusing cryospray treatment to reduce production of airway mucous.

According to an aspect of the invention, there is presented a method forusing cryospray treatment to reset the tissue, causing remodeling of thetreated tissue to normal goblet cell count.

According to an aspect of the invention, there is presented a method forusing cryospray treatment to induce regrowth of cilia.

According to an aspect of the invention, there is presented a method forusing cryospray treatment to treat airway tissue which does not damageunderlying connective tissue and which is less-fibrotic.

According to an aspect of the invention, there is presented a method forcryospray treatment of damaged, inflammatory or hypersecretory airwaytissue comprising a predetermined dose based on endoluminaldiameter/anatomic location in the bronchial tree.

According to an aspect of the invention, there is presented a method forcryospray treatment of damaged, inflammatory or hypersecretory airwaytissue comprising a delivery dose that is configured to produce alimited cryonecrosis that does not extend to the underlying connectivetissue. The depth of cryonecrosis increases with increased dose, inparticular the length of the spray time. Since the connective tissuedepth in the airway is generally related to the diameter of the vessel,this aspect of the invention includes a cryospray dose that is dependenton endoluminal diameter of anatomic location e.g. trachea, main bronchi,lobar and sub-segmental bronchi. Typical endoluminal diameters in thebronchial tree in an average adult are trachea: 18 mm; main bronchus: 12mm; lobar bronchus: 8 mm; segmental bronchus: 6 mm. Yet the thickness ofbronchial tissue layers of relevant to disease processes tends to besubstantially the same irrespective of the endoluminal diameter.Accordingly, according to this aspect of the invention, systems andmethods for ablation of airway tissue are provided which ablate tissuesat substantially constant depths (0.1-0.5 mm) and axial extents (1-2 cm)in airways of widely varying diameter. This is achieved by deliveringpatient- and region-specific quantities of cryogen to the airway basedon limited user inputs.

According to some embodiments within this aspect of the invention, dosetime optionally follows the following guidelines:

TABLE 1 Endoluminal Diameter/Segment Dwell/spray Time 18 mm/Trachea 17to 25 seconds 12 mm/Bronchii (Primary) 11 to 18 seconds  8 mm/Lobar 10to 16 seconds  6 mm/Segmental  8 to 14 seconds

According to an aspect of the invention, a treatment procedure iscomprised of multiple lumen-specific doses in the lung and/or trachea.According to a preferred embodiment, treatment begins at the most distaltargeted sites and progresses in a proximal direction up the respiratorytree. Each dose is applied once to targeted treatment site and allowedto thaw as the bronchoscope is navigated proximally to the next targetedsite. Hand ventilation may be required with or without removingbronchoscope after a number of doses are given and oxygen levels aremonitored and stabilized during treatment. Additionally, more than onetreatment session (also referred to as a procedure day) may be requiredto complete treatment. For instance, ipsilateral bronchi may be treatedon a first procedure day, while contralateral bronchi are treated on asecond procedure day. Thus, embodiments according to this aspect of thepresent invention encompasses the delivery of multiple cryosprays (e.g.1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more cryosprays) to the same region,adjoining regions, or contralateral regions of the bronchial tree, in asingle procedure day or in multiple procedure days (e.g. 2, 3, 4, 5, 6,7, 8, 9, or 10 or more procedure days). In some cases, previouslytreated areas are retreated on subsequent treatment days to providesupplemental ablation or to ablate new tissue growth at a site oftreatment

According to another embodiment of the invention, a dose spacing sheathmay be provided over the bronchoscope. According to this embodiment, thedose spacing sheath extends over the bronchoscope a sufficient length tocover the portion of the scope that is visible to the user/operatoroutside of the patient's body during use, including portions of thescope that are inside the patient's body during part of the treatmentbut that are withdrawn from the patient's body as progressive parts ofthe airway tissue are treated. The exterior of the dose spacing sheathcontains markings that can be used by the operator to gage how far thescope is being moved, i.e., how far the scope is being withdrawn inorder to treat a subsequent location so that doses do not overlapone-another.

Accordingly, to begin treatment, the catheter and scope is advanced tothe most distal segment that will receive treatment. According to apreferred embodiment, each treatment area/location within an airwaysegment is treated with only a single dose. Once the first anatomicallocation is treated, the catheter and scope is withdrawn to a lessdistal anatomic location in the same or a different segment of the lungor trachea, moving in a distal to proximal direction. A dose spacingsheath placed over the bronchoscope may be used to assist the operatorin showing how far the scope and catheter are moved in order to avoidoverlapping doses. Depending on the new location, the dose administeredmay be the same as administered to the first anatomical segment or itmay be different. According to one embodiment of the invention, acircumferential region of untreated tissue is left between regions oftreated tissue. According to this embodiment, regions of contiguoustreated tissue range from 5 mm to 15 mm in length (measured along theaxis of the airway segment, and regions of intervening untreated tissuerange in length from 1 mm to 5 mm.

According to an aspect of the invention, there is presented a method forcryospray treatment of damaged, inflammatory or hypersecretory airwaytissue comprising low pressure cryospray to airway tissue where thepressure of the spray exiting the catheter is less than 5 psi (e.g. 4,3, 2, 1, 0.5, 0.25 psi or less).

According to an aspect of the invention, there is presented a method forcryospray treatment of damaged, inflammatory or hypersecretory airwaytissue where the cryogen exiting the delivery catheter is in the rangeof −150 degrees to −200 degrees Centigrade.

According to an aspect of the invention, there is presented a method forcryospray treatment of damaged, inflammatory or hypersecretory airwaytissue comprising single or multiple treatment sessions whereas one ormore lobes are treated in the same session e.g. a treatment may includethe left lower and middle lobes and one main bronchi; and a subsequentsession may include the right lobe, main bronchi and trachea.

According to an aspect of the invention, there is presented a method forcryospray treatment of damaged, inflammatory, or hypersecretory airwaytissue which is effective to result in reduced mucous/sputum productionand cough. Validated measures of cough-specific quality of life includebut are not limited to the Cough Quality-of-Life Questionnaire (CQLQ) orSt. George Respiratory Questionnaire (SGRQ). Additional tools fordyspnea associated with sputum production include but are not limitedto, patient directed sputum diary cards, such as described by ISWoolhouse; and the Breathlessness, Cough and Sputum Score (BCSS©).

According to an aspect of the invention, there is presented a method forcryospray treatment of damaged, inflammatory or hypersecretory airwaytissue which is effective to improve lung function by 20%, 30%, 50%,70%, 100%, 150% or 200%, as measured by spirometry (e.g.—ForcedExpiratory Volume (FEV1) or FEV1/FVC ratio). Forced Expiratory Volume(FEV1) is the amount of air a patient can blow out of his/her lungs inthe first second. Forced Vital Capacity (FVC) is the largest amount ofair that a patient can blow out after taking the biggest possiblebreath.

According to an aspect of the invention, there is presented a method forcryospray treatment of damaged, inflammatory or hypersecretory airwaytissue which is effective to result in reduced symptoms includingexacerbations requiring medication or hospital stay. There are severalaccepted measurement tools for exacerbations and symptom assessmentincluding but not limited to, the EXACT© (The EXAcerbations of ChronicPulmonary Disease Tool); EXACT PRO©, where PRO is an acronym forPatient-Reported Outcome, and EXACT-RS, daily diary to assessrespiratory symptoms in patients with stable COPD According to a furtherembodiment of the invention, there is a method for cryospray treatmentof damaged, inflammatory or hypersecretory airway tissue which iseffective to result in the reduction of pulmonary biomarkers associatedwith COPD or other disease/damage.

The present invention also relates, in certain aspects, to a sheath orsleeve, designed to fit snugly over the outside surface of abronchoscope during a bronchoscopic procedure such as a procedureaccording to another aspect of the present invention. The exteriorsurface of the sleeve bears markings at pre-determined increments toreflect distance along the length of the sheath which are designed to beused by the practitioner to help gauge and measure movement of thebronchoscope into and out of the patient's airway. The referencemarkings then are used to reference or align to another object such asthe endotracheal tube or rigid bronchoscope.

According to one embodiment, the sheath is made of braided polymerthread/filament. The braid structure is analogous to a Chinese fingerpuzzle, increasing in diameter when compressed longitudinally, andcollapsing/locking down when it is placed under tension. When the sheathis compressed longitudinally, the inner diameter of the sheath expandssignificantly more than its braided diameter, permitting it to slideover scopes or catheters of a broad range of diameters. When permittedto relax and recover to its original braided dimension, and particularlywhen it is placed under tension, it fits snugly on the surface of thescope. This allows the sheath to accommodate and provide insulation andreference markings for multiple scope diameters. The braided sleeveInner Diameter (ID) is intentionally sized smaller than the OuterDiameter (OD) of the preferred bronchoscope such that it expands andfits snuggly to the scope upon insertion. Therefore, the sheath staystightly fixed to the exterior surface of the flexible bronchoscopeduring use, but may be easily loaded and unloaded by pushing the ends ofthe sheath towards one-another, and “inch-worming” the sheath down thelength of the bronchoscope shaft.

The reference markings may be printed on the exterior surface of thesheath, e.g., using a pad printer or other method, or may be braidedinto the sheath, for example using a different colored filament. Ineither event, the markings are set at defined intervals, e.g., 0.5 cm,1.0 cm, 1.5 cm, etc. According to an embodiment of the invention, themarkings may be made in one color to indicate major lengths, e.g., every10 cm, and the markings may be made in a different color to indicateminor lengths, e.g., every 1 cm. Whatever markings are used, they may bemade according to any known method.

According to an embodiment of the invention, the proximal end of thesheath may be cuffed and/or flared and/or bear a hub to facilitateloading and unloading of the sheath from a flexible bronchoscope. A hubmay be a molded or machined plastic component that is joined to thebraided sheath by bonding or insert molding and, optionally, secures thebraided sheath to the bronchoscope, for example by means of a slidablelocking mechanism that can be engaged and disengaged by a user.

According to yet another embodiment, the distal end of the sheath may betapered and or cuffed to facilitate insertion of the sheath-mountedbronchoscope into the sealing gasket of the endotracheal tube, toprovide an atraumatic end so that the sheath does not scythe the tissuewhen moving proximal to distal, and/or to prevent fraying and/orunravelling of the braid. In some cases, the cuff is configured toengage (reversibly or irreversibly) with an introducer element,preferably a rigid, molded or machined polymer component slidablydisposable about the sheath and having a distal portion sized tointerfit with a proximal portion of an endotracheal tube. When engagedwith the endotracheal tube, the introducer element holds a gasket orvalve in the opening of the endotracheal tube in the open position,permitting the sheath to slide freely through the gasket or valve and,consequently, through the endotracheal tube.

According to a cuffed embodiment, the cuffs at either end may bethermally formed from the braided material, or they may be formed from adifferent elastomeric or plastic material and fixed to the end of thebraided material according to one of any number of known methods.According to an alternative embodiment, the distal end of the braidedsleeve may be dipped in or otherwise coated with a flexible material tocreate a distal tip that is stiffer to aid with insertion into anendotracheal tube gasket, but still flexible enough to assemble onto thebronchoscope.

According to an embodiment of the invention, the bronchscopicmeasurement sheath is configured to extend over the flexiblebronchoscope a sufficient length to cover the portion of the scope thatis visible to the user/operator outside of the patient's body duringuse, including portions of the scope that are inside the patient's bodyduring part of the treatment but that are withdrawn from the patient'sbody as progressive parts of the airway tissue are treated. A portion ofthe distal end of the scope may be left uncovered to avoid interruptionof diagnostic and therapeutic devices or gases delivered via thebronchoscope e.g. LN2 cryospray delivery and LN2 gas egress

According to an embodiment of the invention, the bronchoscopicmeasurement sheath provides thermal insulation of portions of the scopethat are inside the patient's body during procedures such as radiofrequency, laser, or cryotherapy to provide protection from thermalinjury. The braided construction and mix of monofilament andmultifilament fibers provide both thermal insulation and a physicalbarrier between the smooth surface of the bronchoscope and endothelium.As the braided construction can comprise of any combination of polymericmaterial, there will also be the insulating contribution provided by thepolymer. According to other embodiments, the braid may be made fromfilaments of other compositions (e.g., polypropylene, nylon, polyester)or the braid may be made from a hybrid of filaments made from PET andother materials.

Turning now to further aspects of the present invention, in one aspectthe present invention relates to a computer-moderated method forlumen-specific and gender-specific cryospray treatment of airway tissuethat is preferably (though not necessarily) damaged, inflammatory, orhypersecretory. The method includes receiving, via a cryosprayuser-interface such as a touch-sensitive display, user inputs of patienttype and anatomical airway segment to be treated, then automaticallydelivering a pre-determined metered cryospray of cryogen based on thepatient type and airway segment entered by the user, which is initiatedby a user input and ends automatically when the predetermined meteredcryospray has been delivered. In various embodiments, the method doesnot require a cryospray instrument to be apposed to airway tissue, andthe method optionally sets different cryospray doses automatically fordifferent airway regions based on their luminal diameter. The patienttype is, in some cases, gender, such that different doses areautomatically set for male and female patients. Optionally oradditionally, treatment spray cannot be initiated until a user hasentered patient information and treatment location into the systemconsole. The method may also involve maintaining a cryospray supply linebetween a cryogen tank and a delivery catheter at a constant temperatureduring cryospray operation, and one or more valves, manifolds, andcatheter interfaces along the supply line may be held at, for example, atemperature warmer than −120° C. The metered cryospray is optionallydelivered via a cryogen delivery catheter having a proximal segment thatis wider than the working channel of a corresponding bronchoscope, and adistal segment that is configured to fit within the working channel ofsaid bronchoscope, said delivery catheter configured to deliver acryospray to the entire circumferential interior of a selectedendoluminal cross-section simultaneously without having to rotate thedelivery catheter, wherein a distal end of the delivery catheter isconfigured with exactly two rows of eight cryogen delivery ports,equally spaced around the perimeter of the catheter, the center line ofthe rows displaced 0.025″ (0.635 mm) from one-another, and each portoffset from an adjacent port of the other row by 20°-25 (e.g. 22.5°).

In another aspect, the present invention relates to an apparatus forcomputer-moderated cryospray of a body lumen (not limited to an airway)that includes pressure maintenance system, a cryogen level monitoringsystem, a catheter attachment apparatus, a fluid path pre-cool function,user-control system for user-control of cryogen flow, a display screen,a cryogen supply line between a cryogen source and said catheterattachment apparatus, a plurality of temperature sensors and heatersassociated with said supply line configured to maintain said supply lineat a constant temperature during cryospray treatment, and an on-boardcontrol system comprising a computer readable medium containing computerreadable instructions for monitoring and controlling cryogen tank filloperation; running pre-procedure system checks; controlling fluid pathpre-cool; and controlling thermal functions during user treatment ofpatients. In some embodiments, the control system will prompt a user toenter a patient type and an anatomical lumen segment for treatment, andwill not to permit cryospray treatment until after said patient type andanatomical airway segment has been entered; the control system isoptionally further configured to cause the apparatus to deliver apre-determined dose of cryospray upon initiation by a user, based on anentered patient type and anatomical airway segment. The cryogen supplyline also optionally includes a cryogen valve, a manifold having a fixedorifice for the escape of cryogen gas, a catheter valve, and a catheterinterface having a fixed orifice for the escape of cryogen gas.

In yet another aspect, the present invention relates to a system with areservoir comprising a cryogen, a fluid path between a the reservoir anda connector port for a cryospray catheter, the fluid path comprising atleast one valve controllable by a processor, an input for a temperaturesensor attached to a cryospray catheter, a graphical output device, auser input device, a non-transitory computer readable medium storinginstructions executable by a processor; and a processor configured to(a) execute the instructions stored on the non-transitory computerreadable medium, (b) receive an input from the temperature sensor, (c)deliver an output to the graphical output device, (d) receive an inputfrom the user input device, and to (e) provide an output to the at leastone valve. The instructions on the computer readable medium includeseveral steps: receiving a user input identifying a sex of a patient andan airway region of the patient to be treated; calculating, based on theuser input and on a temperature input from the cryospray catheter, anamount of cryogen to deliver to ablate an endothelial layer of theairway of the patient; and delivering, through a catheter connected tothe system and into the airway region, the calculated amount of cryogen.The instructions also optionally include comparing a temperaturereceived from the temperature sensor of the catheter to a thresholdtemperature selected based upon the user input of airway location;calculating a rate of change of the temperature received from thetemperature sensor over a time interval and comparing the rate of changeto a threshold rate of change selected based upon the user input;measuring an elapsed time from the opening of the at least one valveduring the step of delivering the cryogen to the catheter and comparingthe timer to a threshold time; and terminating the flow of cryogen byclosing the at least one valve if at least one of the followingconditions is detected: (a) the temperature received from thetemperature sensor is at or below the threshold temperature, (b) therate of change varies by a predetermined amount from the threshold rateof change, (c) the elapsed time equals or exceeds the threshold time,and (d) a user input to sustain the flow of cryogen is terminated beforethe elapsed time reaches 2 seconds, and/or (e) providing an output tothe graphical output device if the flow of cryogen is interrupted and ifneither condition (a) nor condition (c) was detected and, based upon anumber of cryosprays delivered during a treatment session and atemperature output from the temperature sensor, either displaying a userprompt on the graphical output device for an additional spray orterminating the procedure.

In yet another aspect, the present invention relates to a system thatincludes a cryogen source in fluid communication with a cryogen deliverydevice, one or more adjustable pressure valves configured to adjust apressure of the cryogen source in response to a control signal, and acontroller configured to receive an indication of a target pressure,measure the pressure of the cryogen source during an operation of thecryogen delivery device, determine whether the measured pressure matchesthe target pressure, and send the control signal to the one or moreadjustable pressure valves to adjust the pressure of the cryogen sourcetowards the target pressure. The controller optionally determines thetarget pressure by (a) receiving a cooling power measurement indicativeof a cooling power of the cryogen delivery device when the cryogendelivery device is delivering a cryogen, (b) receiving an indication ofthe cryogen source pressure when the cryogen delivery device achieves acooling power corresponding to the cooling power measurement,identifying that the cooling power measurement matches a target coolingpower, and storing the indicated cryogen source pressure as the targetpressure. Steps (a) and (b) are optionally repeated until the coolingpower measurement matches the target cooling power. In some cases, theadjustable pressure valves include a first valve configured to providerough reduction in the pressure of the cryogen source and second andthird valves configured to control pressure vent and pressure buildfunctions of the cryogen source. In this arrangement, the processoroptionally triggers the first valve when the pressure of the cryogensource is greater than a predetermined threshold amount, while thesecond and third valves are optionally responsive to a pulse widthmodulation controller that adjusts its duty cycle based on a controlvoltage provided by the control signal. The control signal may be drivenby a proportional-integral-derivative (PID) control algorithm, which canoptionally adjust the control signal based on the target pressure, acurrent rate of change of pressure, and a pressure history of thecryogen source and which is preferably (though not necessarily)configured to avoid cycling between vent and build operations.

In still another aspect, the present invention relates to a catheter forcryospray treatment of an airway with a proximal interface bayonetconfigured to connect to a cryospray console, an ergonomic plasticbayonet cover configured to interface with the console along with thebayonet, an insulating sheath distributed over a proximal portion of acatheter assembly configured to reside outside a working channel of ascope, a proximal tube portion comprising laser cut metal hypotube andhaving a diameter that exceeds the inner diameter of the working channelof said scope, and a distal tube portion comprising laser cut stainlesssteel hypotube having a diameter and length configured to work in theworking channel of said scope. The catheter includes an outer coveringin the form of a polymeric layer to cover the entire length of thecatheter to provide a fluid tight lumen, and the distal tube portionterminates in a cylindrical segment including an atraumatic tip and,proximal to the tip, a plurality of cryogen delivery ports formed ascircular fenestrations having a diameter of 0.015″ (0.381) within thesegment, the segment comprising exactly two rows of eight cryogendelivery ports, equally spaced around the perimeter of the catheter, thecenter line of the rows displaced 0.025″ (0.635 mm) from one-another,and each port offset from an adjacent port of the other row by 22.5°.Optionally or additionally, the catheter includes a thermocouplesituated at or near a distal tip of the catheter to provide temperaturefeedback to a cryospray console, and/or is configured to deliver cryogento an airway in an annular region about the plurality of fenestrations.The annular region preferably has substantially uniform (e.g. uniformwhen examined visually) axial and radial margins. The catheter can alsoinclude multiple markings on the exterior of the catheter proximal tothe distal segment, which markings are regularly spaced (e.g. separatedby a defined distance such as 1. 2. 5 mm etc.).

In yet another aspect, the present invention relates to a method oftreating a patient by ablating a lung epithelium by cooling an annularregion of an airway to −20° C. to a depth no greater than 0.5 mm from an(inner or luminal) airway surface, for example by delivering a quantityof a cryogen calculated by an automated system to the annular region ofthe airway through a catheter, the catheter terminating in a cylindricalsegment including an atraumatic tip and, proximal to the tip, aplurality of cryogen delivery ports formed as circular fenestrationswithin the segment, the segment comprising exactly two rows of eightcryogen delivery ports, equally spaced around the perimeter of thecatheter, the center line of the rows displaced 0.025″ (0.635 mm) fromone-another, and each port offset from an adjacent port of the other rowby 22.5° and offset from an adjacent port of the same row by 45°. Thecryogen may be liquid nitrogen, and the predetermined quantity may bebased in part upon the region of the airway being treated/ablated. Insome cases, the catheter includes markings on its exterior surface asdescribed above, in which case treatment includes moving the catheter bya fixed distance between applications of cryogen. As one example, afirst system-calculated quantity of cryogen can be delivered to a firstannular region of the airway, the catheter advanced or retracted by thefixed distance, and a second system calculated quantity of cryogen canbe delivered to a second annular region of the airway adjacent to thefirst annular region. The second predetermined quantity of cryogen isdetermined based in part upon a temperature reading after delivery ofthe first predetermined quantity of cryogen, the reading provided by atemperature sensor disposed near the distal end of the catheter, atemperature of the second material on the exterior of the catheter.

In yet another aspect, the present invention relates to a sheathconfigured to be placed over the outer surface of a bronchoscope along aportion of its length during cryospray treatment of an airway or otherbronchoscopic procedure, which includes an elongated tube having a lumenconfigured to receive a bronchoscope, a securing device at one end ofsaid tube configured to secure the sheath to a proximal end of thebronchoscope, and a plurality of markings along a portion of theexternal surface of the tube configured to denote a distance that saidscope is moved relative to a fixed position of a patient, a patientfeature, or other fixed reference point. The markings are, variously,circumferential marker bands, outside the working channel of the scope,and/or associated with printed numbers.

And in yet another aspect, the present invention relates to a method oftreating a patient by: inserting, into an airway of the patient, abronchoscope, at least a portion of the bronchoscope being covered by abraided polymer sheath bearing a plurality of external markingsseparated from one another by a fixed distance, extending, through aworking channel of the bronchoscope, a cryospray delivery catheter intothe airway and delivering a metered cryospray to a first portion of theairway, advancing or retracting the bronchoscope a predetermineddistance, using the plurality of markings on the sheath as an indicatorof the predetermined distance, and delivering a metered cryospray to asecond portion of the airway.

DESCRIPTION OF THE DRAWINGS

The following figures accompany the Detailed Description of theInvention which describes the methods and results of specific examplesof the practice and success of the invention.

FIG. 1 is a perspective view of a cryosurgery system according to anembodiment of the invention;

FIG. 2 is a perspective view of another embodiment of a cryosurgerysystem according to the invention;

FIG. 3 is a perspective view of the interior of an embodiment of acryosurgery system according to an embodiment of the invention;

FIG. 4A is a schematic showing a cryogen storage, delivery and pressurecontrol apparatus according to an embodiment of the invention;

FIG. 4B is a schematic showing a cryogen storage, delivery and pressurecontrol apparatus according to another embodiment of the invention;

FIG. 4C is a three dimensional perspective representation of a cryogenmanifold and valve assembly according to the embodiment shown in FIG.4B.

FIG. 5 is an isometric view of a radial spray catheter according to anembodiment of the invention,

FIG. 6 is a side view of the steel tube proximal construction of acatheter according to the invention with a laser cut pattern that variesto adjust tube flexibility.

FIG. 7 shows a side view of one embodiment of the junction of a largeI.D. hypotube to a small I.D. hypotube shaft

FIG. 8 shows the insulator and connector housing area with the bayonet,according to one embodiment of the invention.

FIG. 9 shows an embodiment of the invention including an S-curvecentering feature on the radial spray catheter containing an axialmarker line that aids in visual positioning of such S-curve with respectto centering of such offset to the scope centerline.

FIG. 10 shows an S-curve centering feature and axial line as viewed bythe scope optics during use.

FIG. 11A is a perspective view, including a blow-up view, of a portionof a cryosurgery system 41 having a cryogen delivery apparatus 42,including bronchoscope 40, gas egress tube 43, and an S-shaped cathetertip 42 exiting the working channel of the bronchoscope.

FIG. 11B shows a blow-up of an alternate embodiment with a straightcatheter tip and no gas egress tube.

FIG. 12 is a flowchart depicting a method in accordance with anexemplary embodiment.

FIGS. 13A-L are exemplary interfaces for performing a setup procedure inaccordance with exemplary embodiments.

FIGS. 14A-P are exemplary interfaces for performing an ablationprocedure in accordance with exemplary embodiments.

FIG. 15 is a block diagram illustrating an electronic computing devicesuitable for use with exemplary embodiments.

FIGS. 16A-16F show various radial spray pattern embodiments that can belocated at the distal tip of the catheter. FIGS. 16G-H illustratecryospray delivery patterns that result from the radial spray designillustrated in FIG. 16D, while FIGS. 16 I-J illustrate cryospraydelivery patterns that result from the radial spray design illustratedin FIG. 16A.

FIG. 17 shows a dose treatment map according to an embodiment of theinvention.

FIG. 18 shows a dose spacing sheath according to an embodiment of theinvention.

FIG. 19A shows temperature curves obtained in an airway model, asmeasured on or near the distal tip of the catheter, when identicalquantities of cryospray are delivered through catheters with varyingstarting temperatures; FIG. 19B shows temperature curves in an airwaymodel when identical cryospray volumes are delivered to a dry workingchannel and a working channel having mucus therewithin.

FIG. 20 shows a bronchoscopic measurement sheath according to anembodiment of the invention, loaded onto the proximal end of abronchoscope

FIG. 21 is a close-up view of a bronchoscopic measurement sheathaccording to an embodiment of the invention, showing an optional flaredproximal end and an optional tapered distal end, with an optionalelastomeric cuff at both ends.

FIG. 22 is a close-up of a bronchoscopic measurement sheath according toanother embodiment of the invention, mounted on a flexible fiber-opticbronchoscope.

FIG. 23 shows a proximal end hub according to an embodiment of theinvention.

FIG. 24 is a close-up view of a bronchoscopic measurement sheathaccording to an embodiment of the invention, specifically showing howthe sheath expands when the ends are forced together.

FIG. 25 shows the proximal end of a bronchoscopic measurement sheathaccording to an embodiment of the invention, next to a flexiblebronchoscope.

FIG. 26 shows the proximal end of a bronchoscopic measurement sheathaccording to an embodiment of the invention mounted on the outside of aflexible bronchoscope.

DETAILED DESCRIPTION OF THE INVENTION

Cryospray Systems and Methods

Certain methods and devices described herein are improvements to thecryospray methods and devices described in co-pending U.S. patentapplication Ser. No. 13/784,596, filed Mar. 4, 2013, entitled“Cryosurgery System,” and co-pending U.S. patent application Ser. No.14/012,320, filed Aug. 28, 2013; each of these applications isincorporated herein by reference in its entirety and for all purposes.

A simplified perspective view of an exemplary cryosurgery system inwhich embodiments of the present invention may be implemented isillustrated in FIGS. 1-3. Cryosurgery system 100 comprises a pressurizedcryogen storage tank 126 to store cryogen under pressure. In thefollowing description, the cryogen stored in tank 126 is liquid nitrogenalthough cryogen may be other materials as described in detail below.The pressure for the liquefied gas in the tank may range from 5 psi to50 psi. According to a more preferred embodiment, pressure in the tankduring storage is 40 psi or less, and pressure in the tank duringoperation is 35 psi or less. According to a more preferred embodiment,pressure in the tank during storage is 35 psi or less and pressureduring operation is 25 psi or less. According to a most preferredembodiment, pressure during operation at normal nitrogen flow is 20±4psi.

Nominal tank pressures according to preferred embodiments of the presentinvention are established to assure that different systems have astandardized energy output, which is, for example, the nominal energyoutput of a standard system used to successfully deliver treatment in ananimal model or in a human patient according to one of the variousembodiments of the present invention; Energy output of individualsystems is assessed using one or more of a standard catheter and/or astandard airway phantom comprising multiple one or more temperaturesensing elements (e.g. one or more thermocouples); temperature changesmeasured by the phantom are used to calculate the total energy outputduring the spray, and multiple sprays may be carried out at varyingpressures to establish a pressure-energy relationship that is then usedto select a pressure value that yields the energy output of the standardsystem, within a predetermined error (e.g. ±5% of standard energyoutput).

In an alternate embodiment, the cryogen pressure may be controlled allthe way to 45 psi to deliver through smaller lumen catheters andadditional feature sets. In such alternate embodiments the pressure inthe tank during storage may be 55 psi or less.

Liquid nitrogen (LN2) resides on the bottom of the tank and liquidnitrogen gas/vapor (GN2) occupies the top portion of the tank. Tanklevel is monitored electronically via a sensor internal to the tank thatchanges value with the level of the liquid inside the tank. This can bedone in a variety of ways, including but not limited to capacitively (anexample being a Rotarex C-Stic), resistively, or by measuringdifferential pressure.

Referring to FIGS. 4A and 4B, the present invention utilizes valves anda pressure sensor 174 to continuously monitor and control the pressureof liquid nitrogen in the tank during use. The console monitors thecurrent pressure of the tank via a pressure sensor 174. The softwarereads the current pressure from the sensor and adjusts the pressureaccordingly. If pressure is too low, the software actuates the pressurebuild circuit valve 176 to increase the pressure to a specifiedthreshold and then turns off. When the pressure is too high, thesoftware turns on the vent valve 178 until the pressure reaches aspecified threshold.

In some cases, system charge pressure is actively controlled by a set ofthree solenoid valves. A cryogenic solenoid valve connected to the headspace is used for rough reduction of tank pressure in cases where tankpressure is significantly above the desired set pressure (>5 psi) orduring fill operations when tank pressure must be completely relieved. Aset of proportional solenoid valves control the pressure vent andpressure build functions. The proportional solenoid valves are driven bya pulse width modulation (PWM) controller which adjusts its duty cyclebased on a control voltage, allowing the valve plunger position to openproportional to the control signal. The control signal is driven by astandard proportional integral derivative (PID) control algorithmexecutable by a central processor of the system. The PID controllercollects data from a precision capacitive pressure sensor and adjuststhe valve control signal based on the current pressure deviation withrespect to the set point, the current rate of change of pressure, andthe pressure history. A PID output control signal determines whetherventing or building operations occur. This control scheme advantageouslyimplements precise pressure regulation while allowing software changesto the pressure set point. The PID controller is tuned (inputs P, I, andD) to provide quick response with minimal overshoot or undershoot, whileavoiding unstable cycling between vent and build operations.

A mechanical relief valve 182 on the console tank ensures that the tankpressure stays in a safe pressure range. Constant pressure monitoringand adjustment, allows the set point on the mechanical relief valve tobe set at 35 psi, allowing for a low tank storage pressure. A redundantburst disk 184 provides protection should the mechanical relief valvefail. For optimal safety, both electronic and mechanical pressure valvesare present to regulate the pressure, providing triple redundancy in theevent of failure. In addition, a redundant pressure switch 180 mayprovide accurate tank pressure readings and is checked during theself-test. In an alternate embodiment, the mechanical relief valve 182may be set at 60 psi, but still allowing to remain a low pressurestorage tank.

The system of the present invention utilizes a manifold assemblyincluding cryogen valve 186, manifold 196, catheter valve 188, defrostvalve 190, fixed orifices 191 and 192, and catheter interface 193 tocontrol liquid nitrogen delivered through the catheter. When the cryogenvalve 186 is actuated, liquid nitrogen exits the tank through the lance194 and proceeds through the cryogen valve 186 to manifold 196 wherefixed orifice 192 is present to allow cold expanded gas and liquidcryogen to exit the line and cool down the internal cryogen circuit.During this precool, the catheter valve 188 downstream of the manifoldremains closed. A data acquisition board collects data from athermocouple 195 located on the manifold body. In the precool function,the system software monitors data from the thermocouple 195, and opensthe cryogen valve 186 to cool the manifold 196 when its temperature isabove the desired set-point. According to a preferred embodiment, fixedorifice 191 is provided on catheter interface 193 to allow venting ofcold expanded gas to exit the line while spraying.

According to a preferred embodiment of the invention, represented inFIGS. 4B and 4C, each of cryogen valve 186, manifold 192, catheter valve188 and catheter interface 193 are provided with a temperaturethermocouple or sensor 195 a and a heater 199 to maintain the cryogenflow path at a constant selected temperature to prevent overcooling ofthe system resulting from the continuous flow of cryogen through thevalves and manifold assembly. According to various embodiments of theinvention, each of the heaters may be controlled to maintain the valves,the manifold and the catheter interface at the same temperature or atdifferent temperatures. According to a preferred embodiment, the systemis set so that the temperature(s) of the valves, manifold, and catheterinterface is/are controlled to be maintained at a temperature greaterthan −120° C. during cryospray treatment. According to a most preferredembodiment, the system is set so that the temperature(s) of the valves,manifold, and catheter interface is/are controlled to be maintained at atemperature of +20° C. during cryospray treatment. According to anotherembodiment, each of the valves, manifold, and catheter interface arecontrolled and maintained at constant temperatures, but the constanttemperatures of each may be different from one or more of the constanttemperatures of the others.

A defrost function is useful for thawing the catheter after cryogenspray, before removal from the scope. A defrost circuit directs gaseousnitrogen from the top of the tank through a heater 187 and defrost valve190 to the catheter 128. When the defrost button on the software screenis pressed, the defrost circuit is activated for a prescribed time (e.g.30 seconds) but can be stopped earlier at the user's discretion. A lowvoltage (24 VDC) DC defrost heater delivers 6 W minimum ofwarming/defrost performance but minimizes variation due to line voltageand limits maximum gas temperature, as compared to the prior art linevoltage (120V) AC heater.

The console of the present invention comes with an insulated quickrelease custom fill hose 164 to fill the tank through the external fillport 166 in a semi-automatic cryogen fill process. A fill port switch onthe console actuates only when the fill hose is in the locked position.During the fill process, liquid nitrogen passes through a filter 172 andtransfer valve 170 en route to the tank. The software automaticallyshuts off the electronic transfer valve 170 when the tank is full andvents the hose prior to removing from the console. According to analternate embodiment, manual filling can take place by mechanicallybypassing the electronic transfer and vent valves with manual valves,thus allowing the tank to be filled without the need for computercontrol.

The catheter is designed to transport liquid nitrogen (or other cryogen)from the console to the patient treatment site. According to oneembodiment, the catheter 1 may contain a bayonet 2 and hub 3 forattachment to the console at its proximal end, a laser cut hypotube tominimize kinking and breaking, and a polymer layer disposed over thehypotube, thereby sealing the catheter 1, and an insulation layer 4 toprotect the user from cold, a strain relief 4 a to help prevent kinkingwhen torqued by users and an atraumatic rounded tip (10) at its distalend to prevent damage to tissue. The hypotube is preferably spiral cut,imparting radial flexibility while maintaining some axial stiffness andpushablility, and the relative flexibility of the hypotube is, in somecases, variable along the length of the catheter 1 through the use of avariable-pitch spiral cut. For instance, the spiral cut may becharacterized by a first, relatively large pitch proximally, and asecond, smaller pitch more distally, allowing the distal end, andparticularly the tip, to bend about a tighter curve than the mostproximal portions of the catheter. The strength and flexibility providedby catheters according to these embodiments allows a user (e.g. aphysician) to retroflex the catheter during a treatment procedure, ifneeded.

The polymer layer may be any suitable flexible polymer that issubstantially gas impermeable (for example fluorinated ethylenepropylene or urethane), and may be disposed over the hypotube in theform of one or more extrusion layers attached by means of heatshrinking, or by means of dip coating, melt coating or spray coating.The catheter package may contain an RFID tag that the user scans priorto use to prevent reuse and track disposable information.

The catheter package may also contain an introducer that providesreinforcement for the catheter and helps prevent kinking during use andwhen placing the catheter into the scope. An alternative constructionlocates the RFID tag on the connector area adjacent to the bayonet, suchthat the RFID tag is scanned by the system when the catheter isconnected to the system.

According to a preferred embodiment, the delivery catheter may beconstructed out of hypotubes of different internal diameters mated toeach other to make a proximal shaft and a distal shaft, with the distalshaft containing the smaller ID. The proximal and distal shafts may bejoined at a connector, which connector can be covered by a molded handleto permit a user to make fine adjustments to the catheter 1. Theproximal shaft may contain a bayonet and hub for attachment to theconsole at its proximal end. The distal shaft preferably has a reducedID to be able to fit through the working channels of a bronchoscope. Thedistal tip of the catheter contains the radial spray pattern holes whichmake up the nozzles configured to deliver the cryogen spray onto thetarget tissue. The end of the catheter may be configured to have roundedtip, preferably made of a welded stainless steel sphere. This roundedtip may help reduce trauma to the tissue during catheter insertion ormanipulation into the body cavities. A thermocouple may be located alongthe catheter shaft, preferably at or near the distal tip of thecatheter, to provide temperature feedback to the control console, forexample to better determine the precise moment that cryospray exits thetip of the catheter. The hypotubes are all laminated with a polymericheatshrink which seals the laser cut pattern from the liquid intended toflow inside the catheter. Additionally, both hypotubes have variablelaser cut patterns which provide rigidity where needed and muchflexibility where needed. This is accomplished by varying the separationof the spiral or repeated cut pattern, as well as varying the shape ofthe pattern itself.

According to an alternative embodiment, the delivery catheter may beconstructed of one or more layers of flexible polyimide, surrounded by astainless steel braid, which is in turn coated with an outer layer ofPebax. It was discovered that that extrusion of Pebax over the stainlesssteel braid allows the Pebax to wick through the pitch of the steelbraid, helping to prevent kinking, breaking, or delamination duringretroflex of the catheter. The Pebax also provides a desirable balancebetween hardness—important for smooth sliding of the catheter andgeneral toughness, and softness, which is important for some degree oftackiness which allows the user to feel the movement of the catheter inthe scope. The pitch of the stainless steel braid is configured to befine enough to afford the required strength, but still allow the Pebaxto wick through. The distal end of the catheter is provided with anatraumatic tip comprised only of Pebax, in the shape of a bullnose. Thisnovel construction allows for retroflex of the catheter without kinking,breaking, or delamination of the catheter. For the purposes of thisinvention, retroflex is used to refer to the ability of a catheter tobend or turn approximately 210° about a radius of curvature of 0.375inch or greater.

FIG. 5 shows the preferred embodiment catheter construction of thecryospray catheter 1 according to the invention. It includes a bayonetconnection 2, catheter connection housing 3, insulation 4, laser cuthypotube with FEP or Pebax heatshrink wrap 5, nozzle connection ofdiminishing inner diameter 6, second smaller ID laser cut hypotube 7with FEP or Pebax heatshrink wrap, radial spray pattern holes 8, spraypattern indicator marking bands 9 (two are shown, but three or more maybe provided, for example, to account for spraying in smaller distalsegments), and rounded tip 10.

By adding very thin layers of metal to the catheter shaft or increasingthe heat transfer coefficient in the shaft by using a hypotube or addinga braided metal for example, the catheter may be constructed to provideoptimal cryo delivery to the tip of the device in a very short cycletime.

FIG. 6 shows a typical hypotube 19 used for the construction of theproximal end of the catheter shaft 5. It typically has a length of 45inches but can vary from 24 to 96 inches in length. The internaldiameter of the tube 19 is usually 0.104 inches but can vary between0.045 to 0.150 inches. In the preferred embodiment, the hypotube 19 maybe laser cut as a spiral, but other variable cuts can be present. Thecuts provide flexibility to the metal tube.

FIG. 7 shows a transition 25 of a large diameter hypotube shaft 19 to asmall diameter laser cut hypotube shaft 8. The transition is so that asmaller diameter can be inserted into the working channel of a scope. Inaddition, the transition from large diameter to small diameter acts as amixing point for the dual phase flow gas and liquid to interact alongthe catheter path and allow for the gas to once again attain thevelocity of the liquid as they travel down the pipe. This transition isreferred to as a “nozzling” transition. This transition can occurbetween two hypotubes, two polymeric shafts or between a coil andhypotube or coil and polymeric shaft.

FIG. 8 shows the insulator 4 and the connector housing 3 added to thecatheter assembly 1.

FIG. 9 is an isometric view of an alternate embodiment catheter with anS-curve centering feature built into its distal tip shape. It shows thebend 12 and the alignment line 29 that is the feature used to visuallyalign the catheter with respect to the scope working channel offset.

FIG. 10 shows the S-curve 12 of an alternate embodiment as seen throughthe scope 20 visualization system. The method of use is to target thearea to be treated by locating the catheter section 11 between themarking bands, then rotating the catheter axially until the axial line29 is visible and horizontal in the line of vision. At this point thecatheter tip is relatively centered with the scope 20 centerline. Thisaxial line is typically created via a pad printed or laser markingprocess.

The preferred radial spray pattern of the catheter distal tip is 2 rowsof holes equally dispersed around the circumference of the shaft, eachrow containing 8 holes of 0.016″ each. The first and second row areseparated along the length of the shaft by a distance of 0.025″ measuredfrom the centerline of the first row to the centerline of the secondrow, and the holes are arranged at 22.5° angles from each other as seenon FIG. 16D. As is shown in FIG. 16G-H, this radial spray design resultsin a pattern of cryospray delivery that is radially and axially uniformabout the circumference of the airway, and that, when used to deliver“metered” cryospray amounts (i.e. cryospray amounts determined by anautomated system of the present invention, delivered utilizing deliveryprotocol generated and executed by an automated system of the presentinvention) permits reliable, repeatable ablation of mucosa without therisk of damage to deeper tissues including airway cartilage; generally,ablation achieved using a radial spray design according to FIG. 16D inconjunction with an automated cryospray system of the present inventionresults in an annular ablation to a depth of between 0.1 and 0.5 mm thatis characterized by a uniform radial and axial margin; the depth ofablation can be increased in some cases while preserving its uniformity(not shown). Importantly, the axial extent of cryospray delivery isgenerally coextensive with the length of the spray pattern of FIG. 16D,and is not axially offset as is observed in other systems. Thus, a userof a system incorporating the tip design of FIG. 16D can be reasonablyassured that, when cryospray is delivered to the airway, it is deliveredin the region in which the tip of the catheter is actually disposed. Theinventors have found that other designs, such as the design of FIG. 16A,generally result in more variable and, frequently, deeper patterns ofablation that are not as advantageous for use in automated systems. Forinstance, FIG. 16I-J shows a cryospray delivery pattern obtained usingthe tip design of FIG. 16A that exhibits “scalloping” both in depth andaxial extent; such scalloping, while appropriate or even useful forcertain applications, is not optimal for mucosal ablation applicationsto treat, for instance, chronic bronchitis, as it raises thesimultaneous risks of overtreatment of certain regions (potentiallycausing damage to airway cartilage) and undertreatment of others(potentially sparing portions of the mucosa contributing to the diseaseprocess).

The holes are located around the circumference of a short stiff sectionof the hypotube without laser cuts, with such section being as small as0.050″ in diameter to allow the hypotube to navigate through aretroflexed bronchoscope or any other areas of tortuosity

Alternative patterns of alternate embodiments are shown on FIGS.16B-16F. The embodiment shown in FIG. 16A has two rows of four roundholes of 0.023″ in diameter. The embodiment shown in FIGS. 16B and 16Chave two rows of three oblong holes that are 2 to 4 times in length ascompared to the diameter of the ends. The embodiment shown in FIG. 16Ehas three rows of six round holes, each having a diameter of 0.022″. Theembodiment shown in FIG. 16F has four rows of eight holes, each having adiameter of 0.016″.

Referring to FIG. 11A, bronchoscope 40 may be positioned in the trachea44, or bronchi—such as the principle bronchi 45 of patient. The catheter48 is placed in the working channel lumen 46 of the scope 40 and exitsthe working channel at the distal tip of the scope. Cryogen deliveryapparatus 42 comprises a radial spray cryogen delivery catheter atdistal end 42, and one or more holes 47. After insertion of the cryogendelivery apparatus into the patient, cryogen is provided to cryogendelivery catheter 48 from a cryogen source. A gas egress tube 43 thatsurrounds the scope may be utilized to provide additional means toevacuate the treatment area of the cryogenic gas out of the patient 49.Passive lumen egress 50 is also present via the management of the airwayto ensure proper venting during the procedure. FIG. 11B shows a blow-upof an alternate embodiment, in which a straight tipped catheter is usedand without a gas egress tube.

Referring to FIG. 18, a dose spacing sheath is shown which is configuredto be placed over the outer surface of a bronchoscope along a portion ofits length during cryospray treatment of an airway or otherbronchoscopic procedure. A dose spacing sheath 401 may be made of anelongated tube 403 having a lumen configured to receive a bronchoscope40, a securing device 405, for example a Tuohy-Borst, at one end of saidtube configured to secure a proximal end of said sheath to a proximalend of the bronchoscope, and a plurality of markings 407 along a portionof the external surface of the tube configured to denote a distance thatsaid scope is moved relative to a fixed position of a patient, a patientfeature, or other fixed reference point. Said markings may becircumferential marker bands outside the working channel of the scopeand may optionally be associated with printed numbers. When aligned witha venting tube (e.g. rigid bronchoscope or endotracheal tube), themarkings provide an extracorporeal proximal reference mark prior todosing. In subsequent doses, the reference markers assist the physicianwhen the scope is moved proximally to the next dosing site so as not tooverlap doses.

FIGS. 13-14 show a variety of screens displayed by the system during anexemplary procedure according to an embodiment of the present invention.A home screen (not shown, but similar to that shown in FIG. 13A, isdisplayed during system power-up and self-test. The self-test can becancelled so the user can proceed directly to filling the console. Oncethe self-test completes, the system proceeds to the next screen.

FIG. 12 depicts an exemplary method 600 for setting up the cryosurgerysystem 100 and performing an ablation procedure. The followingdescription of the steps illustrated in FIG. 12 is supplemented withreferences to exemplary interfaces as shown in FIGS. 13A through 14P.

It is noted that the steps depicted in FIG. 12 are intended to beexemplary only. One of ordinary skill in the art will recognize thatexemplary embodiments may include more, fewer, or different steps.Moreover, unless otherwise noted the ordering of the steps may berearranged.

As an initial matter, a computing device associated with the cryosurgerysystem 100 may be initialized and may initialize the cryosurgery system100. For example, as shown in FIG. 13A, the initialization process mayinvolve performing self-checks, configuring the system to receive a newfill of cryogen, establishing communication between various componentsof the cryosurgery system 100, and retrieving any relevant patientrecords, among other actions.

Once the system has been initialized, at step 605 the computing devicemay receive a treatment identifier. For example, as shown in FIG. 13B,an interface may be presented querying a user as to whether theprocedure is a new therapy or a continuation of a previous treatment. Ifthe procedure is a continuation of a previous treatment, then the usermay be prompted to provide an identification of the previous treatment,and relevant treatment records may be retrieved from the computingdevice's storage. Details of the continuation therapy may be appended tothe record as the therapy is carried out.

If, on the other hand, the therapy is a new therapy, the computingdevice may present an interface allowing a user to either enter a newtherapy identifier, or have the system generate a new therapy identifierautomatically (see FIG. 13C). The new therapy identifier may beassociated with a patient record in the computing device's storage. Ifthe computing system receives a selection indicating that the systemshould generate an identifier, then the system may create a uniqueidentifier based on any appropriate creation scheme (e.g., by selectinga sequential identifier, or generating a random identifier and checkingto ensure that the identifier is not already in use). If the computingdevice receives a selection indicating that the user will enter a customidentifier, then the computing device may present a new interface (e.g.,as shown in FIG. 13D) allowing the user to enter a custom therapyidentifier. Optionally, the computing device may verify that theuser-entered custom therapy identifier is not already in use.

Processing may then proceed to step 610, where the computing device mayreceive procedure settings. The procedure settings represent patientinformation that is used to determine the amount of cryospray to deliverto target areas of the patient's lungs. According to exemplaryembodiments, the cryosurgery system 100 and associated computing deviceare configured to determine a targeted amount of cryospray on the basisof only limited information. For example, as shown in FIG. 13E, theprocedure settings may consist of the patient's gender and lungterminology which defines the airway locations to be selected later. Incombination with a target area of the lung to be treated, theseprocedure settings may be sufficient to determine a targeted amount ofcryospray to be applied. Optionally, the computing device may present aninterface requesting that the procedure settings be confirmed by aphysician, as shown in FIG. 13F.

At step 615, the computing device may receive a catheter identifier thatcorresponds to a type of catheter and/or to a specific catheter. Forexample, each catheter may be provided with a form of identification,such as an RFID tag or a bar code, and the tag or code may be scanned bya suitable scanning device in communication with the computing device.FIG. 13G shows an exemplary interface for receiving a scan of an RFIDtag associated with a catheter.

At step 620, the computing device may determine that the catheter orthermocouple are plugged into the cryosurgery system 100, and/or mayestablish a connection to the catheter and thermocouple. The computingdevice may, for example, identify one or more data ports associated withthe catheter or thermocouple that enable one-way or two-waycommunication between the catheter/thermocouple and the computingdevice. The computing device may display a prompt requesting that thecatheter and thermocouple be connected to the ports, as shown in FIGS.13H-131. Upon detecting the presence of the catheter and thermocouple,and upon establishing communication with the catheter and thermocouple,the computing device may update the display to indicate that thecatheter and thermocouple have been successfully connected (see, e.g.,FIG. 13J).

At step 625, the computing device may perform a cryospray flow check.The computing device may automatically initiate a flow of cryospray bysending a command to the cryosurgery system 100, or may prompt a user tomanually activate the cryospray (as shown in FIG. 13K). The computingdevice may prevent the cryospray from being applied, manually orautomatically, if certain safety parameters are not met. For example,the computing device may read the temperature from the thermocoupleassociated with the catheter prior to performing the cryospray flowcheck. If the thermocouple reports a temperature reading substantiallycorresponding to a body temperature (e.g., about 37° C.), then thecomputing device may determine that the catheter has already beendeployed in the patient's body. Because the flow check is designed tooccur outside of the patient's body, the computing device may, in thiscase, prevent the cryospray from being applied.

The computing device may evaluate the output of the cryosurgery system100 (FIG. 13L) and update the interface with the results of the flowcheck. If the flow is determined to be abnormal (e.g., a flow rateoutside of a predetermined range is detected), then the interface may beupdated to require that the cryosurgery system undergo maintenancebefore continuing. If the flow is determined to be normal, thenprocessing may continue to step 630.

At step 630, the computing device may receive a selection of an anatomicregion and/or subregion for which an ablation procedure will beperformed. The computing device may provide a prompt for allowing a userto enter an identification of a region/subregion to be treated. Theprompt may be textual or, as shown in FIGS. 14A-14E, may be graphical.

At step 635, the computing device may calculate a targeted amount ofcryospray. The calculation may be performed on the basis of theprocedure settings received at step 610 and the region/subregionidentified at step 630. For example, the patient's gender and lungterminology, as well as the target region/subregion, may be provided asinputs to an algorithm or algorithms that relate these values to anamount of cryospray necessary to ablate the tissue in the targetregion/subregion without damaging surrounding tissue. Once the targetedamount of cryospray is determined, processing may proceed to step 640.

At step 640, the computing system may instruct the cryosurgery system100 to deliver the targeted amount of cryospray as calculated in step635. For example, the computing system may automatically initiate thedelivery of cryospray, or may prompt a user to manually initiate thedelivery of cryospray, as shown in FIG. 14F. The computing system mayreceive a signal indicating that the application of cryospray hascommenced.

Once the application of cryospray has commenced, the computing systemmay monitor the delivery of cryospray. The computing system may measurethe amount of cryospray that has been delivered. This may beaccomplished, for example, by calculating the amount of deliveredcryospray based on the amount of time that has elapsed since theapplication of the cryospray commenced and the flow rate as determinedat step 625, or based on the temperature as measured by thethermocouple. In some embodiments, multiple thermocouples may bestrategically located at various locations on the catheter, and themeasurements of the thermocouples may be related to parameters thatallow the measurements to serve as a proxy for spray output. Once theamount of cryospray that has been delivered matches the targeted amountof cryospray, the computing device may automatically terminate thedelivery of cryospray, for example by sending a termination command tothe cryosurgery system 100. Moreover, the application of the spray maybe stopped when the temperature as measured by the thermocoupleindicates that the desired amount of spray has been applied.

During the cryospray delivery procedure, the computing device maymeasure the temperature of the catheter, as related by the thermocoupleaffixed to the exterior of the catheter some distance from the tip. Thecomputing device may stop the spray (e.g., by sending theabove-described termination command) prior to the delivery of thetargeted amount of cryospray under certain conditions. For example, theapplication of cryospray may be terminated if (a) the temperature dropsbelow a safety threshold, (b) the slope of a temperature curve that thedevice generates in real time varies (either too high or too low) from athreshold safety range, or (c) if the duration of spray extends beyond athreshold time.

At step 645, the computing device may identify that the catheter hasthawed. Before performing additional steps (such as re-applyingcryospray or moving the catheter), it may be important to ensure thatthe catheter has returned to a safe temperature to prevent damage to thepatient's tissue or the catheter/thermocouple. Accordingly, thetemperature of the catheter as measured by the thermocouple may bedetermined and compared to a predetermined threshold representing a safetemperature value. If the temperature exceeds the threshold value, thenthe computing device may determine that the catheter has thawed, andprocessing may proceed to step 650. If the temperature does not exceedthe threshold value, then the computing device may wait a predeterminedamount of time (e.g., one second) and re-read the temperature value fromthe thermocouple. Exemplary interfaces for validating that the catheterhas thawed are depicted in FIGS. 14G-14H.

At step 650, the computing device may determine whether the targetedamount of cryospray calculated in step 635 was successfully delivered.As noted above, at step 640 the computing system may monitor variousparameters associated with the catheter and/or thermocouple, whichparameters are preferably used to calculate cryospray parameters and,during the application of cryospray, may be used to assess cryosprayprogress and/or to terminate or interrupt the cryospray if (for example)(a) the temperature drops below a safety threshold, (b) the slope of atemperature curve that the device generates in real time varies (eithertoo high or too low) from a threshold safety range, or (c) if theduration of spray extends beyond a threshold time. If the flow ofcryospray is stopped for these or other reasons before the targetedamount of cryospray is delivered, then the computing device maydetermine at step 650 that the targeted amount of cryospray was notsuccessfully delivered. If step 640 proceeds without interruption, thenthe computing device may determine at step 650 that the targeted amountof cryospray was successfully delivered.

If the determination at step 650 is “no” (i.e., the targeted amount ofcryospray was not successfully delivered), then at step 655 thecomputing device may determine whether to respray the cryospray. Forexample, the computing device may present an interface, such as the onedepicted in FIG. 141, for receiving an indication as to whether torespray the cryospray.

If the determination at step 655 is “no” (i.e., the computing devicedetermines that no respray will occur), then processing may proceed tostep 660 where the treatment is recorded as a partial spray. Forexample, a flag may be set in the patient's record indicating that thetreatment was incomplete, and optionally indicating a degree ofcompleteness of the treatment.

Returning to step 650, if the determination at step 650 is “yes” (i.e.,the targeted amount of cryospray was successfully delivered) and/or ifthe determination at step 655 was “no” (i.e., the computing system didnot determine that a respray should be applied), then processing mayproceed to step 665 where the computing system determines whether anymore areas remain to be treated. For example, the computing system mayread a treatment plan associated with the patient's record, or maypresent a prompt querying whether additional areas remain to be treated.Alternatively, the computing device may present an interface forreceiving a selection of additional areas to be treated, and may furtherpresent an option for ending the process in the event that no more areasremain to be treated.

If the determination at step 665 is “yes” (i.e., there are more areas totreat), then processing may return to step 630 and the computing devicemay receive a new selection of an anatomic region and/or subregion to betreated. The new selection may be the same as a previous selection(i.e., the same area may be selected for multiple treatments). FIGS.14J-14N depict examples of selections of additional regions andsubregions for further treatment.

If the determination at step 665 is “no,” (i.e., there are no more areasto treat), then processing may proceed to step 670 and the computingdevice may end the procedure. As part of step 670, the computing devicemay generate or alter patient records to indicate the status of anytreatments carried out, present prompts instructing the user to removethe catheter from the patient, shut down communication to the catheter,thermocouple, or other parts of the system, and perform any necessaryhousekeeping steps. Exemplary interfaces for ending the procedure aredepicted in FIG. 14O-14P.

One or more of the above-described acts may be encoded ascomputer-executable instructions executable by processing logic. Thecomputer-executable instructions may be stored on one or morenon-transitory computer readable media. One or more of the abovedescribed acts may be performed in a suitably-programmed electronicdevice. FIG. 15 depicts an example of an electronic computing device 700that may be suitable for use with one or more acts disclosed herein.

The computing device 700 may take many forms, including but not limitedto a computer, workstation, server, network computer, Internetappliance, integrated circuit, mobile device, a tablet computer, a smartsensor, custom application specific processing device, etc.

The computing device 700 is illustrative and may take other forms. Forexample, an alternative implementation of the computing device 700 mayhave fewer components, more components, or components that are in aconfiguration that differs from the configuration of FIG. 15. Thecomponents of FIG. 15 and/or other figures described herein may beimplemented using hardware based logic, software based logic and/orlogic that is a combination of hardware and software based logic (e.g.,hybrid logic); therefore, components illustrated in FIG. 15 and/or otherfigures are not limited to a specific type of logic.

The computing device 700 may include a processor 705. Processors 705include devices that execute instructions and/or perform mathematical,logical, control, or input/output operations. The processor 705 mayinclude hardware based logic or a combination of hardware based logicand software to execute instructions on behalf of the computing device700. The processor 705 may include logic that may interpret, execute,and/or otherwise process information contained in, for example, thememory 715. The information may include computer-executable instructionsand/or data that may implement one or more embodiments as describedherein.

The processor 705 may comprise a variety of homogeneous or heterogeneoushardware. The hardware may include, for example, some combination of oneor more processors, microprocessors, field programmable gate arrays(FPGAs), application specific instruction set processors (ASIPs),application specific integrated circuits (ASICs), complex programmablelogic devices (CPLDs), graphics processing units (GPUs), or other typesof processing logic that may interpret, execute, manipulate, and/orotherwise process the information. Moreover, the processor 705 mayinclude a system-on-chip (SoC) or system-in-package (SiP).

The processor 705 may be a Central Processing Unit (CPU) having one ormore processing cores 710. Cores 710 include independent processingunits that are physically or logically separate from one another, andthat are typically configured to perform parallel processing task. Theprocessor 705 may further include one or more coprocessors, and/oron-chip cache. Such a processor 705 may implement the ComplexInstruction Set Computing (CISC) architecture. Examples of suchprocessors 705 include the Celeron®, Pentium®, and Core™ families ofprocessors from Intel Corporation of Santa Clara, Calif., and theAccelerated Processing Unit (APU) and Central Processing Unit (CPU)processors from Advanced Micro Devices (AMD), Inc. of Sunnyvale, Calif.

Alternatively or in addition, the processor 705 of the computing device700 may be a specialized processor having relatively limited processingcapabilities and designed to run in low-power environments. For example,the processor 705 may implement the Reduced Instruction Set Computing(RISC) or Acorn RISC Machine (ARM) architecture. Examples of suchprocessors 705 include the Atom™ family of processors from IntelCorporation of Santa Clara, Calif., the A4 family of processors fromApple, Inc. of Cupertino, Calif., the Snapdragon™ family of processorsfrom Qualcomm Technologies, Inc. of San Diego Calif., and the Cortex®family of processors from ARM Holdings, PLC of Cambridge, England.

The processor 705 may also be a custom processor.

The computing device 700 may include one or more tangible non-transitorycomputer-readable storage media for storing one or morecomputer-executable instructions or software that may implement one ormore embodiments of the invention.

The non-transitory computer-readable storage media may be, for example,the memory 715 or the storage 750. The memory 715 may comprise a RAMthat may include RAM devices that may store the information. The RAMdevices may be volatile or non-volatile and may include, for example,one or more DRAM devices, flash memory devices, SRAM devices,zero-capacitor RAM (ZRAM) devices, twin transistor RAM (TTRAM) devices,read-only memory (ROM) devices, ferroelectric RAM (FeRAM) devices,magneto-resistive RAM (MRAM) devices, phase change memory RAM (PRAM)devices, or other types of RAM devices. Examples of memory 715 includeSecure Digital™ (SD) memory from the SD Association, as well as SingleInline Memory Modules (SIMMs) and Double Inline Memory Modules (DIMMs)from a variety of manufacturers. The memory 715 may also be a custommemory.

The computing device 700 may include a virtual machine (VM) 720 forexecuting the instructions loaded in the memory 715. A virtual machine720 may be provided to handle a process running on multiple processorsso that the process may appear to be using only one computing resourcerather than multiple computing resources. Virtualization may be employedin the computing device 700 to dynamically share infrastructure andresources in the electronic device. Multiple VMs 720 may be resident ona single computing device 700.

A hardware accelerator 725, may be implemented in an ASIC, FPGA, or someother device. Hardware accelerators 725 include specialized logicimplemented in hardware to perform functions that would otherwise beexecuted more slowly by software. Accordingly, the hardware accelerator725 may be configured to reduce the general processing time of thecomputing device 700.

The computing device 700 may include a network interface 730 tointerface with a network through one or more types of connections. Thenetwork may be, for example, a Local Area Network (LAN), Wide AreaNetwork (WAN) or the Internet. The network interface 730 may be, forexample, a network interface controller (NIC) for establishing a wiredconnection to a computer network, a fiber optic interface for connectingto a fiber optic network, a cable interface for connecting to a cabletelevision network, a telephone jack for connecting to a telephonenetwork, a power-line interface for connecting to a power-linecommunications network, an area network connection for receivinginformation on LAN or WAN links (e.g., T1, T3, 56 kb, X.25), a broadbandconnection for connecting to, for example, an integrated servicesdigital network (ISDN), a Frame Relay connection, an asynchronoustransfer mode connection (ATM), wireless connections (e.g.,802.11x-compatible networks), high-speed interconnects (e.g.,InfiniBand, gigabit Ethernet, Myrinet), or some combination of any orall of the above.

The network interface 730 may include a built-in network adapter,network interface card, personal computer memory card internationalassociation (PCMCIA) network card, card bus network adapter, wirelessnetwork adapter, universal serial bus (USB) network adapter, modem orany other device suitable for interfacing the computing device 700 toany type of network capable of communication and performing theoperations described herein.

The computing device 700 may include hardware and/or software forconnecting to one or more input devices 735, such as a keyboard, amulti-point touch interface, a pointing device (e.g., a mouse), agyroscope, an accelerometer, a haptic device, a tactile device, a neuraldevice, a microphone, or a camera that may be used to receive inputfrom, for example, a user. Note that the computing device 700 mayinclude hardware or software for interacting with other suitable I/Operipherals.

The input devices 735 may be configured to provide input that isregistered on a visual display device 740. A graphical user interface(GUI) 745 may be shown on the display device 740. The GUI 745 maycorrespond to the GUIs depicted in any of FIGS. 13A-14P. Note that othertypes of output devices, besides visual display devices, may be employedwith the computing device 700.

The computing device 700 may also interface with the cryosurgery system100 for receiving input from, and providing output to, the cryosurgerysystem 100. The computing device 700 may issue instructions to thecryosurgery system 100, and may perform any or all of the stepsdescribed in FIG. 12. Alternatively or in addition, the computing device700 may be integral with the cryosurgery system 100.

A storage device 750 may also be associated with the computing device700. Storage devices 750 include devices that persistently store data onone or more tangible, non-transitory computer-readable mediums. Thestorage device 750 may store information, including data and/orcomputer-executable instructions that may implement one or moreembodiments of the invention. The information may be executed,interpreted, manipulated, and/or otherwise processed by the processor705. The storage device 750 may include, for example, a magnetic disk,optical disk (e.g., CD-ROM, DVD player), random-access memory (RAM)disk, tape unit, and/or flash drive.

The storage device 750 (as well as other components depicted in FIG. 15)may be accessible to the processor 705 via an I/O bus.

The storage device 750 may further store files 755, applications 760,and an operating system (OS) 765. Examples of OSes 765 may include theMicrosoft® Windows® operating systems, the Unix and Linux operatingsystems, the MacOS® for Macintosh computers, an embedded operatingsystem, such as the Symbian OS, a real-time operating system, an opensource operating system, a proprietary operating system, operatingsystems for mobile electronic devices, or other operating system capableof running on the electronic device and performing the operationsdescribed herein. The operating system 765 may be running in native modeor emulated mode.

Still further, the storage device 750 may store logic for controllingthe cryosurgery system 100, such as logic embodying the cryosurgeryprocess 600 described in FIG. 12.

FIG. 13A-L shows a series of Procedure Set-up Screens according to anembodiment of the invention which initiates the steps needed to performa procedure with the system of the invention. The Procedure Set-upscreen may consist of Tank Level Indicator, and various selectableprocedure settings, including but not limited to Patient Type selection(e.g., gender, weight-based, age-based, or any other patient category orinformation that may be used as a basis for delivery of proper cryospraydose), Vent Method, and Egress Reminder selection. The Procedure Set-upscreen may also consist of text or symbols to guide the user through theset-up of consumables for the procedure. Once this set-up is complete,the user can proceed to the next screen. Alternatively, if the user isaccessing the system to fill the console or to service the console, theuser may access those functional screens by selecting a drop-down menu(not shown).

The catheter is scanned by placing the RFID tag on the scanner on theside of the console. When a catheter is successfully scanned, theCatheter ID appears on the screen, and the screen guides the user to thenext step. Scanning a catheter initiates the Pre-Cooling process.According to another embodiment, an RFID tag may be provided in a partof the catheter itself, preferably in the connector housing, or “hub”,so that it is automatically detected when it is plugged into theconsole. According to this alternative embodiment, the RFID scanner isplaced in the console proximate to the location where the catheter isplugged into the console, so that it automatically reads an RFID that islocated in the connector housing of a catheter when a catheter isplugged into the console.

The set up screen contains a list of requirements that must be met priorto moving to the next screen. The list may include but is not limitedto:

Vent Method or Gas Egress Path Confirmed—The system acknowledges thatthe gas egress path has been checked.

Valid Catheter—The system acknowledges the catheter was successfullyscanned.

Catheter Inserted—The system detects when the user successfully insertsa catheter into the control panel.

Gender Selected—the system acknowledges that the patient gender has beenselected. Any type of patient category that may serve as a basis fordelivery of proper cryospray dose may be used, including gender,weight-based, age-based, etc.

When the system is pre-cooling, a state indicator box stating“Precooling System” is displayed.

OK Button—pressing this button enables progression to the next screen,provided all needs have been met. Once all the requirements on theprocedure set-up screen are met, pressing the next button takes the userto the Treatment Screen.

Treatment Screens, shown in FIG. 14A-P guide users through a procedurefor lung treatment, generally include a bronchial tree schematic 501including anatomy labels 503 for each segment that may be treated. Doselocation labels 504, dose status indicators 505, cryogen tank volumeremaining display 507, total spray indicator 509, state indicators 511,test spray button 513 and defrost button 515. The user selects the doselocation label button for the location that will receive the treatment.Selection of one of the label buttons set the dose time for that spray.

When one of the anatomy label buttons is selected, the systemautomatically sets the dose time for that treatment location and patientgender (or other patient type or category, according to system design).

Once a dose is completed, the first dose status indicator for thattreatment site will change colors. The number of dose status indicatorsfor a particular dose location button depends on the length of thesegment. For example, the Trachea dose location button 504 shown in FIG.14 has six dose status indicators 505. This means that there are sixpotential treatment locations in the trachea. When the Trachea isselected for treatment, the status indicators will change colors one ata time, as each different site in the trachea is completed. If anincomplete dose is delivered, the indicator will not change colors. Bycontrast, the left bronchial segment #9 location button has only twodose status indicators because it is a much shorter segment andtypically requires only two separate doses to cover the entire treatablesegment. When a spray dose is initiated, this indicator may count downto zero. Once it reaches zero, the spray automatically stops and anaudible beep may sound.

A thermocouple or other temperature sensing element (e.g. a flex circuittemperature sensor) is preferably disposed on the catheter near thedistal tip, to provide temperature information to the console. Thetemperature information is used in several of processes described above:temperature information is used to determine the quantity of cryosprayto be delivered by the system, to determine when the cryospray exits thetip of the catheter and to control the delivery of dosing, and toprovide feedback to the system during the delivery of cryospray, as thesystem is preferably configured to interrupt the flow of cryospray ifthe measured temperature decreases below a threshold, or if the rate ofchange of the measured temperature varies from a standard rate ofchange. As is shown in FIG. 19A, the temperature of the catheter at thetime the cryospray is initiated may significantly impact any changes intissue temperature caused by the cryospray; accordingly, the system maydecrease the cryospray dose delivered over the course of a sequence ofcryosprays, and this decrease may be caused, at least in part, by aprogressive decrease in the catheter temperature over the course ofmultiple treatments.

FIG. 19B shows that the rate of temperature change, as measured by atemperature sensor disposed on the catheter, can vary depending on thepresence or absence of mucus within the working channel; thus,temperature information of the catheter is used in preferred embodimentsis used to assess the rate of temperature change during the delivery ofcryospray, and if the rate of change varies beyond a threshold valuefrom a standard rate of change, or if the elapsed time during thecryospray exceeds a threshold time, the system may interrupt thecryospray.

According to certain embodiments, then, the timing of the spray dose maybe started from the moment cryospray leaves the catheter, based onfeedback from the thermocouple, rather than from the time the userdepresses the pedal.

The defrost button may be pressed to facilitate removal of a frozencatheter from a scope or other manipulation tool, if it is necessary toremove it before the catheter would naturally thaw. When the DEFROSTbutton is engaged, the DEFROST Indicator will appear. DEFROST will runfor a predetermined amount of time. To interrupt the defrost operationbefore the predetermined time has elapsed, the user need only press thedefrost button a second time.

The Test Spray button may be pressed if the user wants to demonstratethe spray outside of the patient.

The End Procedure button may be pressed once the procedure is complete.Pressing this button may lead the user to a procedure summary report,which may summarize the doses and locations for that procedure day.

Venting of Nitrogen gas is achieved through passive venting. Beforebeginning treatment and at the discretion of the treating physician,proper passive venting tube type and size should be determined. A rigidbronchoscope or endotracheal vent tube may provide an annular vent areawhere the scope passes through the center of the tube.

A scope Introducer may be provided in the catheter kit to aidintroduction of the catheter into the scope and to reduce catheterkinking. The tapered end of the introducer should be placedapproximately 1 cm into the working channel of the scope or until anybuilt in mechanical stop engages into the introducer.

A sheath (referred to herein as a “dose spacing sheath”) may be placedon the outer surface of the flexible bronchoscope to aid in discreetplacement of doses to prevent overlapping doses when multiple doses aredelivered in an anatomical lumen of the same diameter.

A flexible bronchoscope is introduced through the nose or mouth asappropriate and the airway is inspected before starting the procedure.The user then navigates the bronchoscope to the targeted site andpositions the bronchoscope so that the targeted treatment site isviewed.

Once the bronchoscope has been advanced to the target treatment site,the catheter may be fed through the introducer and into the workingchannel of the bronchoscope. Once the catheter has been properlysituated at the target site, the user then selects the anatomy locationbuttons on the Treatment screen, based on which anatomical location willbe treated.

Prior to delivering a dose, the system may prompt the user to confirmgas egress path.

To initiate cryospray, the user presses and holds the foot pedal. Thesystem will spray until the earlier of a predetermined temperature ismeasured by the catheter or a predefined time based on the anatomy andpatient type/category/gender screen selections has elapsed.

During the spray, the monitor may count down the time remaining on thedose. Once the dose is complete, the display may indicate the dose iscomplete, and the user can then move to the next dose location and pressthe location on the user interface.

If the spray is stopped before an adequate dose is delivered, the systemmay not acknowledge it as a dose and the user may be advised toredeliver that dose.

As an example of the use of the invention in the right lung, and withreference to FIG. 17, after making the appropriate console gender andanatomic selections, the user would navigate to most distal point of RB9(Right Lateral basal), activate the spray, then wait for the spray toautomatically stop after the prescribed dose, then wait for thaw. Theuser would then move the catheter and bronchoscope proximally andnavigate to RB10 (Right Posterior basal), indicate that treatmentlocation on the user interface, and repeat the procedure steps (i.e.,initiate spray, wait for it to automatically stop, then wait for thaw).The user would then move the catheter and bronchoscope proximally to RB8(Right Anterior basal), and again repeat. The user would then navigateto RB7 (Right Medial basal), and repeat. After spraying the BasalSegments, the user would then move the catheter to the Right Lower Lobe,indicate that treatment location on the user interface, and repeat theprocedure steps with the lobar treatment time pre-programmed into thesystem. In each anatomy location, there may be more than one spray/dosedepending on the length of the segment, but no more than one dose/sprayon the same site. This may continue until all viable segments, lobar andbronchi locations have been treated.

For segments that are long enough for more than one spray/dose, the usermay spray more than one spray/dose, but no more than one dose/spray onthe same site. An example in Right Lobar Bronchi, the user would proceedas follows: navigate to most distal point of RLL (Right Lower Lobar),note the marking on the Dose Spacing Sheath relative to a fixed point,e.g. endotracheal tube, spray, thaw, back up using the markings on theDose Spacing Sheath, spray dose number two in RLL, thaw. Move thecatheter and the bronchoscope proximally into the bronchus intermedius.Hand ventilation may be required with or without removing bronchoscope.

In the main bronchi, there may be more than one spray/dose depending onthe length of the segment but no more than one dose/spray on the samesite. Again, moving the catheter and bronchoscope in adistal-to-proximal direction, and after changing the console anatomicsetting to bronchi, the user would note the marking on the Dose SpacingSheath relative to a fixed point, e.g. endotracheal tube, spray, thaw,back up using the markings on the Dose Spacing Sheath, spray dose numbertwo, thaw and repeat until main bronchi and bronchus intermedius aretreated. Hand ventilation may be required with or without removingbronchoscope after a number of doses are given.

In the trachea, there may be more than one spray/dose depending on thelength of the trachea, but no more than one dose/spray on the same site.Starting at the main carina, moving the catheter and bronchoscope in adistal to proximal direction note the marking on the Dose Spacing Sheathrelative to a fixed point, e.g. endotracheal tube, spray, thaw, back upusing the markings on the Dose Spacing Sheath, spray dose two, thaw andrepeat until an appropriate length of the trachea is treated. Handventilation may be required with or without removing bronchoscope aftera number of doses are given.

Bronchoscopic Sheath for Measuring and Spacing

Referring to FIG. 21, a bronchoscopic measurement sheath is shown whichis configured to be placed over the outer surface of a flexiblefiber-optic bronchoscope along a portion of its length during abronchoscopic procedure. Bronchoscopic measurement sheath 401 may bemade of an elongated tube 403 having a lumen configured to receive abronchoscope 40, a securing device 405, for example a Tuohy-Borst, atone end of said tube configured to secure a proximal end of said sheathto a proximal end of the bronchoscope. According to other embodiment,the securing device is a hub (see, e.g., FIG. 4) fixed to a proximal endof the sheath. The sheath preferably bears a plurality of markings 407along a portion of the external surface of the tube configured to denotea distance that said scope is moved relative to a fixed position of apatient, a patient feature, or other fixed reference point. Saidmarkings may be circumferential marker bands outside the working channelof the scope and may optionally be associated with printed numbers. Whenaligned with a venting tube (e.g. rigid bronchoscope or endotrachealtube), the markings provide an extracorporeal proximal reference markprior to dosing. In subsequent doses or treatments, the referencemarkers assist the physician when the scope is moved to new treatmentlocations. In the case of dose spacing, the reference markers assist thephysician so as not to overlap doses.

A bronchoscopic measurement sheath may be placed on the outer surface ofthe flexible bronchoscope to provide reference markings to aidpractitioner in measuring movement of the bronchoscope into and out ofthe patient's airway during diagnostic or therapeutic bronchoscopy

A bronchoscopic measurement sheath may be placed on the outer surface ofthe flexible bronchoscope to aid in discreet placement of doses toprevent overlapping doses when multiple doses are delivered in ananatomical lumen of the same diameter.

FIG. 21 shows a close up of an embodiment of a bronchoscopic measurementsheath according to an embodiment of the invention in which a proximalend of the sheath is cuffed or hubbed and a distal end of the sheath iscuffed and tapered. The optional hub at the proximal end is configuredto aid with loading of the sheath onto a bronchoscope, and the optionaltaper at the distal end is configured to assist with introduction of asheath-loaded bronchoscope into an endotracheal tube.

According to various embodiments, the sheath may be made of a braidedPET (polyethylene terephthalate) polymer monofilament, and the markingsare printed on the exterior of the sheath. According to otherembodiments, the braid may be made from filaments of other compositions(e.g., polypropylene, nylon, polyester) or the braid may be made from ahybrid of filaments made from PET and other materials. According to apreferred embodiment, the braid is a 72-carrier construction in a 1 over2 under 2 pattern, the 72 elements comprising 24 elements of 0.0052″ PETmonofilament at each end, and 48 elements of 85/24 PET multifilament (85denier/24 filaments). The material may be braided onto a 0.076″ acetalsubstrate core at 38 ppi (pics per inch). According to otherembodiments, the braid may be comprised of up to 150 elements ofdifferent diameter filaments from 0.004″ to 0.01 and up to 50 ppi (picsper inch). Alternatively, the braid is a 26 ppi (measured afterconstruction) braid formed over a 2 mm mandrel, having 12 carriers ineach direction (24 total) with 2 ends each of 0.006″ (0.015 mm)monofilament and another 12 carriers in each direction (24 total)comprising 440 denier monofilament, and is heat-set at 340° F. (171.1°C.) for five minutes.

As shown in FIG. 21, either or both ends of the sheath may be formedwith a cuff or bonded to prevent or inhibit fraying and/or unraveling ofthe braid and assist in insertion and removal from the scope.

The end cuffs may be a heat-fused end of the braid itself, or it may bea separate elastomeric (e.g., polyurethane, silicon, etc.) or rigidplastic hub fixed or bonded to the end of the braid. In the case aproximal hub is used, it is preferably shaped to fit the tapered portionof the bronchoscope that connects the working end to the hand piece.According to one embodiment, the hub may be a separate elastomericelement that sandwiches the end of the braid. The hub may be affixed tothe braid according to any known methods, including heat bonding, jointbonding, ultra violet light cure, adhesive, or mechanical bonding, suchas dipping. According to a preferred embodiment, the hub may be formedwith an annular recess (see FIG. 4) configured to receive theheat-sealed edge of the braid. Once the end of the braided tube has beeninserted into the annular recess of the hub, adhesive may be dispensedto fill the annular space that receives the braid, bonding the braidinto the annular recess. As shown in FIG. 21, the distal end may betapered for atraumatic insertion in anatomy. According to anotherembodiment, the distal end may be made have greater stiffness than theremainder of the braid to assist with insertion of the bronchoscope andmounted measurement sheath into the sealing gasket of an endotrachealtube or other laryngeal mask airway, preventing the sheath from bucklingand retracting on itself and the bronchoscope as it passes through thetight passage.

FIG. 22 shows an embodiment of a bronchoscopic measurement sheathmounted on the proximal end of a bronchoscope. The proximal portion ofthe braided sheath may be a heat-fused end of the braid itself, or itmay have a separate elastomeric (e.g., polyurethane, silicon, etc.) orrigid plastic element fixed to the end of the braid in order to slidethe sheath onto the scope and fix it in place (see, e.g., FIGS. 6 and7). According to a preferred embodiment, the proximal end has athermoplastic molded component or “hub” (see, e.g., FIG. 4) molded ontothe braid and having tapered interior profile to accommodate the taperedjunction between the proximal end of the flexible fiber opticbronchoscope (the “working portion”) and the handpiece.

FIG. 24 shows how the braid of the sheath is configured to expand andopen when the two ends of the sheath are forced together. In order toadvance the sheath over the bronchoscope prior to a procedure, or towithdraw the sheath from the bronchoscope after a procedure, the userneed only squeeze one end of the sheath tightly against thebronchoscope, and advance the other end toward the fixed end. When thepinched/fixed end is released, the sheath will relax in that direction.However, when one end of the sheath is pulled, the configuration of thebraid causes the sheath to tighten tightly around the bronchoscope.Accordingly, the braid of the sheath causes the sheath to work like aChinese finger puzzle. Accordingly, the sheath will not slide off thebronchoscope as it is being advanced into the endotracheal tube and downa patient's airway. According to a preferred embodiment, the sheath ispackaged in a pre-loaded compressed state, so that when it is removedfrom the packaging for use it is already in the compressed,braid-expanded state which facilitates its application onto the outsidesurface of the scope.

FIG. 25 shows an embodiment of the braided sheath according to theinvention, bearing a rigid plastic cuff at the proximal end, next to aflexible bronchoscope onto which it might be loaded. FIG. 26 shows anembodiment of the braided flexible sheath according to the inventionloaded onto the outside surface of a flexible bronchoscope, with therigid plastic cuff at the proximal end of the sheath tightly fitted tothe tapered portion of the bronchoscope that connects the working end ofthe bronchoscope to the handpiece of the bronchoscope.

According to an embodiment of the invention for dose spacing, theinvention was initially designed for use in connection with cryospraytreatment of a patient's airway using a bronchoscope to allow a user tocarefully monitor how far the bronchoscope was being advanced intoand/or withdrawn from a patient's airway to ensure that all desiredportions of the airway received treatment, but no portion of the airwayreceived more than a single treatment. A flexible bronchoscope isintroduced through the nose or mouth as appropriate and the airway isinspected before starting the procedure. The user then navigates thebronchoscope to the targeted site and positions the bronchoscope so thatthe targeted treatment site is viewed. The dose spacing sheath providesdose spacing guidance when referenced against a fixed reference pointsuch as an endotracheal tube, to allow the bronchoscopist not to dosethe same anatomical location more than once.

For example, using the dose spacing sheath to assist with cryospraytreatment in Right Lobar Bronchi, the user would navigate sheath-mountedbronchoscope to most distal point of RLL (Right Lower Lobar), noting themarking on the dose spacing sheath relative to a fixed point, e.g.endotracheal tube. The user would then initiate a spray treatment, allowthe area to thaw, then withdraw the bronchoscope a discrete distanceusing the markings on the dose spacing sheath, and then spray a seconddose at a second non-overlapping location in the in RLL. The sameprocedure would be used at any location within the airway to make surethat multiple contiguous or nearly contiguous regions are treatedwithout overlap.

While use of the bronchoscopic measurement sheath and the concept ofdose spacing is described herein in the context of cryospray therapy, itcan be used for any type of airway treatment in which measure ofdistance is important.

While use of the bronchoscopic measurement sheath is described herein inthe context of airway reference measurement and treatment it can be usedfor any type of bronchoscopic or endoscopic treatment in which measureof distance is important.

In addition to assisting with dosing, the dose spacing sheath of theinvention may be used as a measuring device for any bronchoscopicprocedure to document the location of lesions, strictures, treatmentsites or length of airway segments.

CONCLUSION

While the examples presented above are focused on treatment of theairway, the systems, methods, and principles illustrated thereby will beunderstood by skilled artisans to be applicable to cryotherapy of otherorgan systems and conditions in which delivery of cryogen to a sitewithin a body lumen, including the esophagus, stomach, duodenum, smallintestine, large intestine, rectum, uterus, fallopian tube, etc. isdesired. Additionally, the automated cryospray systems and cathetersdescribed above can be adapted to treat such organ systems, andcatheters and systems so adapted, as well as the use of such systemsgenerally, are within the scope of the present invention.

The phrase “and/or,” as used herein should be understood to mean “eitheror both” of the elements so conjoined, i.e., elements that areconjunctively present in some cases and disjunctively present in othercases. Other elements may optionally be present other than the elementsspecifically identified by the “and/or” clause, whether related orunrelated to those elements specifically identified unless clearlyindicated to the contrary. Thus, as a non-limiting example, a referenceto “A and/or B,” when used in conjunction with open-ended language suchas “comprising” can refer, in one embodiment, to A without B (optionallyincluding elements other than B); in another embodiment, to B without A(optionally including elements other than A); in yet another embodiment,to both A and B (optionally including other elements); etc.

The term “consists essentially of means excluding other materials thatcontribute to function, unless otherwise defined herein. Nonetheless,such other materials may be present, collectively or individually, intrace amounts.

As used in this specification, the term “substantially” or“approximately” means plus or minus 10% (e.g., by weight or by volume),and in some embodiments, plus or minus 5%. Reference throughout thisspecification to “one example,” “an example,” “one embodiment,” or “anembodiment” means that a particular feature, structure, orcharacteristic described in connection with the example is included inat least one example of the present technology. Thus, the occurrences ofthe phrases “in one example,” “in an example,” “one embodiment,” or “anembodiment” in various places throughout this specification are notnecessarily all referring to the same example. Furthermore, theparticular features, structures, routines, steps, or characteristics maybe combined in any suitable manner in one or more examples of thetechnology. The headings provided herein are for convenience only andare not intended to limit or interpret the scope or meaning of theclaimed technology.

Certain embodiments of the present invention have described above. Itis, however, expressly noted that the present invention is not limitedto those embodiments, but rather the intention is that additions andmodifications to what was expressly described herein are also includedwithin the scope of the invention. Moreover, it is to be understood thatthe features of the various embodiments described herein were notmutually exclusive and can exist in various combinations andpermutations, even if such combinations or permutations were not madeexpress herein, without departing from the spirit and scope of theinvention. In fact, variations, modifications, and other implementationsof what was described herein will occur to those of ordinary skill inthe art without departing from the spirit and the scope of theinvention. As such, the invention is not to be defined only by thepreceding illustrative description.

What is claimed is:
 1. A method for treating a condition in an airway ofa lung of a patient, comprising: advancing an energy transfer device toa target region in the airway; and transferring energy between theenergy transfer device and the target region in an amount sufficient toremodel dysfunctional epithelial cells in the target region withouteither direct or indirect visual confirmation and in an amountconfigured to elicit a primarily regenerative healing response, suchthat the condition is improved.
 2. The method of claim 1, wherein theairway comprises the trachea, the bronchus, the bronchiole, or thealveolus, or any combination thereof.
 3. The method of claim 1, whereinthe epithelial cells comprise ciliated cells or goblet cells, or both.4. The method of claim 1, further comprising inserting a flexibleworking channel into the lung and wherein advancing the energy transferdevice comprises advancing the energy transfer device with or throughthe working channel.
 5. The method of claim 1, wherein advancing theenergy transfer device to the target region comprises navigating throughthe airway utilizing a 3-D virtual map.
 6. The method of claim 1,wherein advancing the energy transfer device comprises navigating thelung according to a treatment map user interface.
 7. The method of claim1, wherein the energy comprises ablative energy, thermal energy, ornon-thermal energy, or any combination thereof.
 8. The method of claim1, wherein transferring energy comprises remodeling the dysfunctionalepithelial cells.
 9. The method of claim 1, wherein transferring energycomprises preserving an extracellular matrix of the dysfunctionalepithelial cells.
 10. The method of claim 1, wherein the amount of theenergy transferred, which is sufficient to affect dysfunctionalepithelial cells, is calculated.
 11. The method of claim 1, whereintransferring energy is performed on a mucosal layer or epithelial layerof the airway at the target region at a depth of at most 0.5 mm from asurface of the airway.
 12. The method of claim 1, further comprising,during a same procedure or different procedures, re-treating the targetregion within the airway, treating a different target region within theairway, or treating a different target region within a different airway,or any combination thereof.
 13. A method for treating symptoms of COPDin an airway of a lung of a patient, comprising: advancing an energytransfer device to a target region in the airway; and transferringenergy between the energy transfer device and the target region in anamount sufficient to remodel epithelial cells in the target regionwithout either direct or indirect visual confirmation and substantiallywithout a reparative scarring healing response in the target region,such that one or more of the symptoms are improved.
 14. The method ofclaim 13, further comprising inserting a flexible working channel intothe lung and wherein advancing the energy transfer device comprisesadvancing the energy transfer device with or through the workingchannel.
 15. The method of claim 13, wherein the energy comprisesablative energy, thermal energy, or non-thermal energy, or anycombination thereof.
 16. The method of claim 13, wherein remodeling theepithelial cells comprises preserving an extracellular matrix of theepithelial cells.
 17. The method of claim 13, wherein the amount of theenergy transferred, which is sufficient to remodel epithelial cells, iscalculated.
 18. The method of claim 13, wherein the one or more of thesymptoms comprise one or more symptoms of chronic bronchitis.
 19. Amethod for reducing mucus production in an airway of a lung of apatient, comprising: advancing an energy transfer device to a targetregion in the airway; and transferring energy between the energytransfer device and the target region in an amount sufficient to remodelepithelial cells in the target region without either direct or indirectvisual confirmation and in an amount configured to elicit a primarilyregenerative healing response, such that mucus production is reduced.20. The method of claim 19, further comprising inserting a flexibleworking channel into the lung and wherein advancing the energy transferdevice comprises advancing the energy transfer device with or throughthe working channel.
 21. The method of claim 19, wherein the energycomprises ablative energy, thermal energy, or non-thermal energy, or anycombination thereof.
 22. The method of claim 19, wherein transferringenergy comprises preserving an extracellular matrix of the epithelialcells.
 23. The method of claim 19, wherein the amount of the energytransferred, which is sufficient to reduce epithelial cells, iscalculated.
 24. The method of claim 19, wherein the epithelial cellscomprise ciliated cells or goblet cells, or both.
 25. A method fortreating a condition in an airway of a lung of a patient, comprising:advancing an energy transfer device to a target region in the airway;and transferring energy between the energy transfer device and thetarget region in an amount sufficient to remodel epithelial cells in thetarget region without necessitating either direct or indirect visualconfirmation and substantially without a reparative scarring healingresponse in the target region, such that the condition is improved. 26.The method of claim 25, wherein the energy comprises ablative energy,thermal energy, or non-ablative energy, or any combination thereof. 27.The method of claim 25, wherein transferring energy comprises preservingan extracellular matrix of epithelial cells.
 28. The method of claim 25,wherein transferring energy is performed to a predetermined depth of atmost 0.5 mm from the surface of the airway from a surface of the airwayat the target region within a mucosal layer or an epithelial layer, orboth layers.
 29. The method of claim 25, wherein the amount of theenergy transferred, which is sufficient to alter epithelial cells, iscalculated.
 30. The method of claim 25, wherein the epithelial cellscomprise ciliated cells or goblet cells, or both.